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ResearchIn-Press PreviewAgingCardiology Open Access | 10.1172/jci.insight.195508

PCPE-1 promotes cardiac fibrosis with aging and obesity

Yung-Ting Hsiao,1 Yohko Yoshida,2 Hirotsugu Tsuchimochi,3 Jingyuan Tang,1 Tin May Aung,1 Chun-Han Chang,1 Agian Jeffilano Barinda,1 Zhihong Li,1 Nur Syakirah Binti Othman,1 Tom Yoshizaki,1 Yiwei Ling,4 Shujiro Okuda,4 Manabu Abe,5 Seiya Mizuno,6 Satoru Takahashi,6 Takayuki Inomata,7 Hidetaka Kioka,8 Yasushi Sakata,8 Daichi Maeda,2 Yuya Matsue,2 Takaaki Furihata,2 Hiroshi Iwata,2 James T. Pearson,3 Kinya Otsu,9 Kenneth Walsh,10 Akihito Ishigami,11 Tohru Minamino,2 and Ippei Shimizu1

1Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

4Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

5Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

6Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan

7Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

8Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan

9Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan

10Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

11Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

Find articles by Hsiao, Y. in: PubMed | Google Scholar

1Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

4Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

5Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

6Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan

7Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

8Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan

9Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan

10Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

11Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

Find articles by Yoshida, Y. in: PubMed | Google Scholar

1Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

4Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

5Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

6Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan

7Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

8Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan

9Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan

10Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

11Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

Find articles by Tsuchimochi, H. in: PubMed | Google Scholar |

1Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

4Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

5Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

6Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan

7Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

8Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan

9Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan

10Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

11Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

Find articles by Tang, J. in: PubMed | Google Scholar

1Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

4Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

5Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

6Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan

7Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

8Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan

9Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan

10Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

11Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

Find articles by Aung, T. in: PubMed | Google Scholar

1Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

4Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

5Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

6Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan

7Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

8Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan

9Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan

10Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

11Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

Find articles by Chang, C. in: PubMed | Google Scholar

1Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

4Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

5Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

6Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan

7Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

8Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan

9Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan

10Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

11Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

Find articles by Barinda, A. in: PubMed | Google Scholar

1Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

4Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

5Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

6Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan

7Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

8Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan

9Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan

10Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

11Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

Find articles by Li, Z. in: PubMed | Google Scholar

1Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

4Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

5Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

6Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan

7Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

8Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan

9Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan

10Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

11Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

Find articles by Othman, N. in: PubMed | Google Scholar

1Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

4Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

5Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

6Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan

7Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

8Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan

9Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan

10Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

11Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

Find articles by Yoshizaki, T. in: PubMed | Google Scholar

1Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

4Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

5Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

6Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan

7Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

8Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan

9Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan

10Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

11Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

Find articles by Ling, Y. in: PubMed | Google Scholar

1Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

4Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

5Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

6Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan

7Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

8Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan

9Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan

10Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

11Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

Find articles by Okuda, S. in: PubMed | Google Scholar |

1Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

4Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

5Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

6Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan

7Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

8Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan

9Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan

10Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

11Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

Find articles by Abe, M. in: PubMed | Google Scholar |

1Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

4Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

5Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

6Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan

7Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

8Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan

9Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan

10Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

11Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

Find articles by Mizuno, S. in: PubMed | Google Scholar

1Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

4Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

5Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

6Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan

7Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

8Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan

9Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan

10Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

11Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

Find articles by Takahashi, S. in: PubMed | Google Scholar |

1Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

4Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

5Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

6Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan

7Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

8Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan

9Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan

10Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

11Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

Find articles by Inomata, T. in: PubMed | Google Scholar

1Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

4Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

5Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

6Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan

7Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

8Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan

9Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan

10Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

11Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

Find articles by Kioka, H. in: PubMed | Google Scholar

1Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

4Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

5Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

6Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan

7Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

8Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan

9Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan

10Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

11Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

Find articles by Sakata, Y. in: PubMed | Google Scholar

1Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

4Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

5Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

6Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan

7Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

8Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan

9Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan

10Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

11Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

Find articles by Maeda, D. in: PubMed | Google Scholar

1Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

4Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

5Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

6Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan

7Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

8Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan

9Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan

10Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

11Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

Find articles by Matsue, Y. in: PubMed | Google Scholar

1Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

4Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

5Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

6Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan

7Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

8Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan

9Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan

10Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

11Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

Find articles by Furihata, T. in: PubMed | Google Scholar

1Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

4Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

5Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

6Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan

7Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

8Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan

9Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan

10Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

11Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

Find articles by Iwata, H. in: PubMed | Google Scholar

1Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

4Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

5Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

6Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan

7Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

8Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan

9Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan

10Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

11Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

Find articles by Pearson, J. in: PubMed | Google Scholar |

1Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

4Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

5Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

6Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan

7Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

8Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan

9Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan

10Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

11Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

Find articles by Otsu, K. in: PubMed | Google Scholar

1Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

4Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

5Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

6Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan

7Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

8Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan

9Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan

10Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

11Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

Find articles by Walsh, K. in: PubMed | Google Scholar |

1Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

4Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

5Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

6Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan

7Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

8Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan

9Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan

10Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

11Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

Find articles by Ishigami, A. in: PubMed | Google Scholar

1Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

4Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

5Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

6Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan

7Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

8Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan

9Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan

10Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

11Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

Find articles by Minamino, T. in: PubMed | Google Scholar

1Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

4Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

5Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

6Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan

7Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

8Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan

9Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan

10Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

11Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

Find articles by Shimizu, I. in: PubMed | Google Scholar

Published April 9, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.195508.
Copyright © 2026, Hsiao et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published April 9, 2026 - Version history
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Abstract

Heart failure with preserved ejection fraction (HFpEF) is a multifactorial disease that develops in several clinical settings. Despite its complex pathogenesis, evidence indicates a central role for fibrosis in the progression of left ventricular (LV) diastolic dysfunction (LVDD). Through exploratory research into brown adipose tissue (BAT)-derived adipokines (BATokines), we identified a secreted-type pro-fibrotic protein, procollagen C-endopeptidase enhancer-1 (PCPE-1), whose expression increased in BAT with aging. PCPE-1 promotes the cleavage of procollagens and is a critical initiator of fibrillogenesis. This molecule was increased in the plasma of aged mice. In addition to aging, dietary obesity led to an increase in PCPE-1 expression in the LV of mice. Both systemic and BAT-specific PCPE-1 depletion ameliorated LV fibrosis and LVDD in the obese HFpEF model. Our data also showed that age-associated LVDD was ameliorated in the systemic PCPE-1 knockout mouse model fed with a normal chow diet. Conversely, the overexpression of PCPE-1 expression in BAT was shown to lead to aggravation of LV fibrosis and LVDD. Mechanistically, we found reactive oxygen species (ROS)/DNA damage/c-Fos/c-Jun signaling resulted in an increased production of PCPE-1 in brown adipocytes. These results indicate PCPE-1 may represent a druggable target for aging- and obesity-related HFpEF.

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