Regulation of cardiac fibroblast-mediated maladaptive ventricular remodeling by β-arrestins
Philip, Jennifer L.; Xu, Xianyao; Han, Mei; Akhter, Shahab A.; Razzaque, Abdur
Cardiac fibroblasts (CF) play a critical role in post-infarction remodeling which can ultimately lead to pathological fibrosis and heart failure. Recent evidence demonstrates that remote (non-infarct) territory fibrosis is a major mechanism for ventricular dysfunction and arrhythmogenesis. β-arrestins are important signaling molecules involved in β-adrenergic receptor (β-AR) desensitization and can also mediate signaling in a G protein independent fashion. Recent work has provided evidence that β-arrestin signaling in the heart may be beneficial, however, these studies have primarily focused on cardiac myocytes and their role in adult CF biology has not been well studied. In this study, we show that β-arrestins can regulate CF biology and contribute to pathological fibrosis. Adult male rats underwent LAD ligation to induce infarction and were studied by echocardiography. There was a significant decline in LV 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- fold in CF isolated at 8 and 12 weeks post-MI and β-arrestin expression was significantly increased. β-adrenergic signaling was uncoupled in the post-MI CF and β-agonist-mediated inhibition of collagen synthesis was lost. Knockdown of β-arrestin1 or 2 in the post-MI CF inhibited transformation to myofibroblasts as well as basal and TGF-β-stimulated collagen synthesis. These data suggest that β-arrestins can regulate CF biology and that targeted inhibition of these signaling molecules may represent a novel approach to prevent postinfarction pathological fibrosis and the transition to HF.
Philip, Jennifer L., & Xu, Xianyao, & Han, Mei, & Akhter, Shahab A., & Razzaque, Abdur. (July 2019). Regulation of cardiac fibroblast-mediated maladaptive ventricular remodeling by β-arrestins. PLOS ONE, (14:7), p.e0219011. Retrieved from http://hdl.handle.net/10342/8299
Philip, Jennifer L., and Xu, Xianyao, and Han, Mei, and Akhter, Shahab A., and Razzaque, Abdur. "Regulation of cardiac fibroblast-mediated maladaptive ventricular remodeling by β-arrestins". PLOS ONE. 14:7. (e0219011.), July 2019. September 29, 2020. http://hdl.handle.net/10342/8299.
Philip, Jennifer L. and Xu, Xianyao and Han, Mei and Akhter, Shahab A. and Razzaque, Abdur, "Regulation of cardiac fibroblast-mediated maladaptive ventricular remodeling by β-arrestins," PLOS ONE 14, no. 7 (July 2019), http://hdl.handle.net/10342/8299 (accessed September 29, 2020).
Philip, Jennifer L., Xu, Xianyao, Han, Mei, Akhter, Shahab A., Razzaque, Abdur. Regulation of cardiac fibroblast-mediated maladaptive ventricular remodeling by β-arrestins. PLOS ONE. July 2019; 14(7) e0219011. http://hdl.handle.net/10342/8299. Accessed September 29, 2020.