PCPE-1 promotes cardiac fibrosis with aging and obesity
Yung-Ting Hsiao, Yohko Yoshida, Hirotsugu Tsuchimochi, Jingyuan Tang, Tin May Aung, Chun-Han Chang, Agian Jeffilano Barinda, Zhihong Li, Nur Syakirah Binti Othman, Tom Yoshizaki, Yiwei Ling, Shujiro Okuda, Manabu Abe, Seiya Mizuno, Satoru Takahashi, Takayuki Inomata, Hidetaka Kioka, Yasushi Sakata, Daichi Maeda, Yuya Matsue, Takaaki Furihata, Hiroshi Iwata, James T. Pearson, Kinya Otsu, Kenneth Walsh, Akihito Ishigami, Tohru Minamino, Ippei Shimizu
Yung-Ting Hsiao, Yohko Yoshida, Hirotsugu Tsuchimochi, Jingyuan Tang, Tin May Aung, Chun-Han Chang, Agian Jeffilano Barinda, Zhihong Li, Nur Syakirah Binti Othman, Tom Yoshizaki, Yiwei Ling, Shujiro Okuda, Manabu Abe, Seiya Mizuno, Satoru Takahashi, Takayuki Inomata, Hidetaka Kioka, Yasushi Sakata, Daichi Maeda, Yuya Matsue, Takaaki Furihata, Hiroshi Iwata, James T. Pearson, Kinya Otsu, Kenneth Walsh, Akihito Ishigami, Tohru Minamino, Ippei Shimizu
View: Text | PDF
Research Article Aging Cardiology

PCPE-1 promotes cardiac fibrosis with aging and obesity

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 diastolic dysfunction (LVDD). Through exploratory research into adipokines derived from brown adipose tissue (BAT), we identified a secreted-type profibrotic 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, 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–KO mouse 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 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.

Authors

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

×

Figure 4

The BATokine PCPE-1 contributes to the pathogenesis of HFpEF.

Options: View larger image (or click on image) Download as PowerPoint
The BATokine PCPE-1 contributes to the pathogenesis of HFpEF. Littermate...
Littermate control (Con) or BAT Pcolce-KO mice were fed with a high-fat diet (HFD) and studied during 41–47 weeks of age (middle-aged). BAT adeno-associated virus (AAV) encoding Pcolce was injected in the BAT of C57BL/6NCrSlc mice fed with an HFD and studied at 15 weeks of age (mature adult). BAT-PCOLCE KI mice were also fed with an HFD and studied at 23–25 weeks of age (mature adult). (A, F, and J) Western blot analysis of mouse (A and F) or human (J) PCPE-1 expression in the heart of the indicated mice. (B, G, and K) Echocardiographic findings in mice: E/e’ (marker for diastolic dysfunction), IVSTd (interventricular septum thickness), LVDs (left ventricular systolic dimension), FS (fractional shortening) (n = 14, 10 for B), (n =7, 7 for G), and (n = 8, 7 for K). (C, H, and L) Masson’s trichrome stain of the heart and its quantification (n =5, 5 for C), (n = 5, 6 for H), and (n = 4, 6 for L) in mice. Scale bar: 50 μm. (D, I, and M) ELISA for collagen type I (shown as Collagen 1) testing hearts in mice (n = 9, 10 for D), (n = 5, 6 for I), and (n = 8, 7 for M). (E) Experimental design of the AAV-Pcolce mouse. (N) Schematic demonstrating that ROS/DNA damage/c-Fos/c-Jun signaling upregulates PCPE-1 expression in BAT with aging. PCPE-1 produced from BAT promotes fibrosis in the heart. All data were analyzed by an independent-samples t test. Data information: Representative Masson’s trichrome–stained images from 1 series of observations (C, H, and L), and other data were obtained from 1 representative analytical experiment out of at least 2 independent experiments showing similar results. *P < 0.05, **P < 0.01. Values are presented as mean ± SEM. NS = not significant.