Regulation of cardiac fibroblast-mediated maladaptive ventricular remodeling by ß-arrestins

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Shahab A. Akhter (Creator)

Mei Han (Creator)

Jennifer L. Philip (Creator)

Abdur Razzaque (Creator)

Xianyao Xu (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Cardiac fibroblasts (CF) play a critical role in post-infarction remodeling which can ultimately\r\nlead to pathological fibrosis and heart failure. Recent evidence demonstrates that remote\r\n(non-infarct) territory fibrosis is a major mechanism for ventricular dysfunction and arrhythmogenesis. ß-arrestins are important signaling molecules involved in ß-adrenergic receptor\r\n(ß-AR) desensitization and can also mediate signaling in a G protein independent fashion.\r\nRecent work has provided evidence that ß-arrestin signaling in the heart may be beneficial,\r\nhowever, these studies have primarily focused on cardiac myocytes and their role in adult\r\nCF biology has not been well studied. In this study, we show that ß-arrestins can regulate\r\nCF biology and contribute to pathological fibrosis. Adult male rats underwent LAD ligation to\r\ninduce infarction and were studied by echocardiography. There was a significant decline in\r\nLV function at 2–12 weeks post-MI with increased infarct and remote territory fibrosis by histology consistent with maladaptive remodeling. Collagen synthesis was upregulated 2.9-\r\nfold in CF isolated at 8 and 12 weeks post-MI and ß-arrestin expression was significantly\r\nincreased. ß-adrenergic signaling was uncoupled in the post-MI CF and ß-agonist-mediated\r\ninhibition of collagen synthesis was lost. Knockdown of ß-arrestin1 or 2 in the post-MI CF\r\ninhibited transformation to myofibroblasts as well as basal and TGF-ß-stimulated collagen\r\nsynthesis. These data suggest that ß-arrestins can regulate CF biology and that targeted\r\ninhibition of these signaling molecules may represent a novel approach to prevent postinfarction pathological fibrosis and the transition to HF.

Additional Information

Publication

Other

Language: English

Date: 2023

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