A cardiac fibroblast-enriched micropeptide regulates inflammation in ischemia/reperfusion injury
Youchen Yan, Tingting Zhang, Xin He, Tailai Du, Gang Dai, Xingfeng Xu, Zhuohui Chen, Jialing Wu, Huimin Zhou, Yazhi Peng, Yan Li, Chen Liu, Xinxue Liao, Yugang Dong, Jing-song Ou, Zhan-Peng Huang
Youchen Yan, Tingting Zhang, Xin He, Tailai Du, Gang Dai, Xingfeng Xu, Zhuohui Chen, Jialing Wu, Huimin Zhou, Yazhi Peng, Yan Li, Chen Liu, Xinxue Liao, Yugang Dong, Jing-song Ou, Zhan-Peng Huang
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Research Article Cardiology Cell biology

A cardiac fibroblast-enriched micropeptide regulates inflammation in ischemia/reperfusion injury

Abstract

Inflammation is a critical pathological process in myocardial infarction. Although immunosuppressive therapies can mitigate inflammatory responses and improve outcomes in myocardial infarction, they also increase the risk of infections. Identifying novel regulators of local cardiac inflammation could provide safer therapeutic targets for myocardial ischemia/reperfusion injury. In this study, we identified a previously uncharacterized micropeptide, which we named Inflammation Associated MicroPeptide (IAMP). IAMP is predominantly expressed in cardiac fibroblasts, and its expression is closely associated with cardiac inflammation. Downregulation of IAMP promotes, whereas its overexpression prevents, the transformation of cardiac fibroblasts into a more inflammatory phenotype under stressed/stimulated conditions, as evidenced by changes in the expression and secretion of proinflammatory cytokines. Consequently, loss of IAMP function leads to uncontrolled inflammation and worsens cardiac injury following ischemia/reperfusion surgery. Mechanistically, IAMP promotes the degradation of HIF-1α by interacting with its stabilizing partner HSP90 and, thus, suppresses the transcription of proinflammatory genes downstream of HIF-1α. This study underscores the significance of fibroblast-mediated inflammation in cardiac ischemia/reperfusion injury and highlights the therapeutic potential of targeting micropeptides for myocardial infarction.

Authors

Youchen Yan, Tingting Zhang, Xin He, Tailai Du, Gang Dai, Xingfeng Xu, Zhuohui Chen, Jialing Wu, Huimin Zhou, Yazhi Peng, Yan Li, Chen Liu, Xinxue Liao, Yugang Dong, Jing-song Ou, Zhan-Peng Huang

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Figure 5

IAMP regulates HIF-1α protein expression.

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IAMP regulates HIF-1α protein expression. (A) qPCR analysis of mRNA leve...
(A) qPCR analysis of mRNA levels of IAMP, Il6, Mmp3, and Cxcl1 in control and IAMP-KD cardiac fibroblasts with or without PDTC (10 �M) treatment. n = 3 for each group. (B) Venn diagram showing the numbers of differentially expressed gene in IL-17–stimulated IAMP-KD cardiac fibroblasts. (C) Pathway enrichment analysis of the upregulated genes using the NCI pathway interaction database. (D) STRING interaction network of HIF-1α and NF-κB with proteins of upregulated genes. The yellow and blue boxes represent HIF-1α– and NF-κB–interacting proteins, respectively. (E) Western blotting and quantification of HIF-1α protein (n = 3) and qPCR analysis of Hif1a mRNA (n = 4) in the IAMP-KD cardiac fibroblasts. (F) Western blotting and quantification of HIF-1α protein (n = 3) and qPCR analysis of Hif1a mRNA (n = 4) in the IAMP-OE cardiac fibroblasts. (G) Western blotting and quantification of HIF-1α protein (n = 3) and qPCR analysis of Hif1a mRNA (n = 3) in the cardiac fibroblasts isolated from IAMP-KO and Ctrl mice. *P < 0.05; **P < 0.01; ***P < 0.001, by 2-tailed Student’s t test (F and G) or ANOVA with Tukey’s correction (A and E).