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Chronic activation of the myocardial renin angiotensin system (RAS) elevates the local level of angiotensin II (Ang II) thereby inducing pathological cardiac hypertrophy, which contributes to heart failure. However, the precise underlying mechanisms have not been fully delineated. Herein we report a novel paracrine mechanism between cardiac fibroblasts (CF)s and cardiomyocytes whereby Ang II induces pathological cardiac hypertrophy. In cultured CFs, Ang II treatment enhanced exosome release via the activation of Ang II receptor types 1 (AT 1 R) and 2 (AT 2 R), whereas lipopolysaccharide, insulin, endothelin (ET)-1, transforming growth factor beta (TGFβ)1 or hydrogen peroxide did not. The CF-derived exosomes upregulated the expression of renin, angiotensinogen, AT 1 R, and AT 2 R, downregulated angiotensin-converting enzyme 2, and enhanced Ang II production in cultured cardiomyocytes. In addition, the CF exosome-induced cardiomyocyte hypertrophy was blocked by both AT 1 R and AT 2 R antagonists. Exosome inhibitors, GW4869 and dimethyl amiloride (DMA), inhibited CF-induced cardiomyocyte hypertrophy with little effect on Ang II-induced cardiomyocyte hypertrophy. Mechanistically, CF exosomes upregulated RAS in cardiomyocytes via the activation of mitogen-activated protein kinases (MAPKs) and Akt. Finally, Ang II-induced exosome release from cardiac fibroblasts and pathological cardiac hypertrophy were dramatically inhibited by GW4869 and DMA in mice. These findings demonstrate that Ang II stimulates CFs to release exosomes, which in turn increase Ang II production and its receptor expression in cardiomyocytes, thereby intensifying Ang II-induced pathological cardiac hypertrophy. Accordingly, specific targeting of Ang II-induced exosome release from CFs may serve as a novel therapeutic approach to treat cardiac pathological hypertrophy and heart failure. [ABSTRACT FROM AUTHOR]

Aims: Deubiquitinating enzymes (DUBs) appear to be critical regulators of a multitude of processes such as proliferation, apoptosis, differentiation, and inflammation; however, the potential roles of DUBs in the heart remain to be determined. This study was aimed to explore the role of a DUB, ubiquitin carboxyl terminal hydrolyase L1 (UCH-L1) in maladaptive cardiac remodeling and dysfunction. Methods and Results: Maladaptive cardiac remodeling and dysfunction were induced in mice by transverse aortic constriction (TAC). UCH-L1 expression was transiently increased and then declined near to the basal level while impairment of cardiac function proceeded. The upregulation of UCH-L1 was observed in cardiac myocytes and fibroblasts. In primary culture of cardiac fibroblasts, UCH-L1 was upregulated by platelet-derived growth factor (PDGF)-BB and PDGF-DD. Adenoviral overexpession of UCH-L1 inhibited the PDGF-induced cardiac fibroblast proliferation without affecting the activation of mitogen activated protein kinases (MAPKs), Akt, and signal transducers and activators of transcription 3 (STAT3). Further signaling dissection revealed that PDGF-BB posttranscriptional upregulated p21WAF1/Cip1 protein expression, which was inhibited by rapamycin, an activator of autophagy via suppressing mammalian target of rapamycin (mTOR), rather than MG132, a proteasome inhibitor. Overexpression of UCH-L1 enhanced PDGF-BB-induced mTOR phosphorylation and upregulation of p21WAF1/Cip1 protein expression while suppressed autophagic flux in cardiac fibroblasts. Conclusion: UCH-L1 facilitates PDGF-BB-induced suppression of autophagic degradation of p21WAF1/Cip1 proteins in cardiac fibroblasts, which may serve as a novel negative feedback mechanism in the control of cardiac fibroblast proliferation contributing to cardiac fibrosis and dysfunction. [ABSTRACT FROM AUTHOR]