Disruption of angiotensin II type 1 (AT1) receptor prolonged life span in mice. Since aging-related decline in skeletal muscle function was retarded in Atgr1a−/− mice, we examined the role of AT1 receptor in muscle regeneration after injury. Administration of AT1 receptor blocker irbesartan increased the size of regenerating myofibers, decreased fibrosis, and enhanced functional muscle recovery after cryoinjury. We recently reported that complement C1q, secreted by macrophages, activated Wnt/β-catenin signaling and promoted aging-related decline in regenerative capacity of skeletal muscle. Notably, irbesartan induced M2 polarization of macrophages, but reduced C1q expression in cryoinjured muscles and in cultured macrophage cells. Irbesartan inhibited up-regulation of Axin2, a downstream gene of Wnt/β-catenin pathway, in cryoinjured muscles. In addition, topical administration of C1q reversed beneficial effects of irbesartan on skeletal muscle regeneration after injury. These results suggest that AT1 receptor blockade improves muscle repair and regeneration through down-regulation of the aging-promoting C1q-Wnt/β-catenin signaling pathway.

Background:The consequences of calpain activation after myocardial infarction (MI) are not fully elucidated. Results: Post-MI remodeling was exacerbated in calpastatin-deficient hearts, and calpain activation disrupted N-cadherinbased cell adhesions. Conclusion: Unregulated activation of calpains contributes to progression of post-MI remodeling. Significance: Pharmacological intervention of the calpain-calpastatin system will be a promising strategy in the treatment of post-MI remodeling.

The octapeptide angiotensin II (Ang II) plays a homeostatic role in the regulation of blood pressure and water and electrolyte balance, and also contributes to the progression of cardiovascular remodeling. Ang II activates Ang II type 1 (AT1) receptor and type 2 (AT2) receptor, both of which belong to the seven-transmembrane, G protein-coupled receptor family. Most of the actions of Ang II such as promotion of cellular prolifaration, hypertrophy, and fibrosis are mediated by AT1 receptor. However, in some pathological situations, AT2 receptor shows an increase in tissue expression and functions to antagonize the actions induced by AT1 receptor. Recent studies have advanced our understanding of the molecular mechanisms underlying receptor activation and signal transduction of AT1 and AT2 receptor in the cardiovascular system.

Abstract-The angiotensin II (Ang II) type 1 (AT 1 ) receptor mainly mediates the physiological and pathological actions of Ang II, but recent studies have suggested that AT 1 receptor inherently shows spontaneous constitutive activity even in the absence of Ang II in culture cells. To elucidate the role of Ang II-independent AT 1 receptor activation in the pathogenesis of cardiac remodeling, we generated transgenic mice overexpressing AT 1 receptor under the control of ␣-myosin heavy chain promoter in angiotensinogen-knockout background (AT 1 Tg-AgtKO mice). In AT 1 Tg-AgtKO hearts, redistributions of the G␣ q11 subunit into cytosol and phosphorylation of extracellular signal-regulated kinases were significantly increased, compared with angiotensinogen-knockout mice hearts, suggesting that the AT 1 receptor is constitutively activated independent of Ang II. As a consequence, AT 1 Tg-AgtKO mice showed spontaneous systolic dysfunction and chamber dilatation, accompanied by severe interstitial fibrosis. Progression of cardiac remodeling in AT 1 Tg-AgtKO mice was prevented by treatment with candesartan, an inverse agonist for the AT 1 receptor, but not by its derivative candesartan-7H, deficient of inverse agonism attributed to a lack of the carboxyl group at the benzimidazole ring. Our results demonstrate that constitutive activity of the AT 1 receptor under basal conditions contributes to the cardiac remodeling even in the absence of Ang II, when the AT 1 receptor is upregulated in the heart. (Hypertension. 2012;59:627-633.) • Online Data Supplement Key Words: ARB Ⅲ cardiac dysfunction Ⅲ fibrosis Ⅲ G protein-coupled receptor Ⅲ inverse agonist T he angiotensin II (Ang II) type 1 (AT 1 ) receptor is a 7 transmembrane spanning G protein-coupled receptor (GPCR), and the activation of AT 1 receptor is involved in regulating pathophysiological processes of the cardiovascular system. In principle, the AT 1 receptor is activated on binding to Ang II, which is produced systemically or locally after sequential proteolytic processing. However, recent studies demonstrated that the AT 1 receptor inherently shows spontaneous constitutive activity even in the absence of Ang II in cultured cells. [1][2][3] GPCRs are structurally unstable and show significant levels of spontaneous activity in an agonistindependent manner. 4 In addition, we and others demonstrated that the AT 1 receptor can be activated by mechanical stress independent of Ang II 5-7 through conformational switch of the receptor. 1 These observations have highlighted the inverse agonist activity of AT 1 receptor blockers (ARBs) as a drug-specific property that can inhibit Ang II-independent constitutive activity and mechanical stress-induced receptor activation. 1,2,5,8 In a mouse model, mechanical stressinduced AT 1 receptor activation led to the development of cardiac hypertrophy independent of Ang II, and treatment with inverse agonists for the AT 1 receptor-attenuated cardiac hypertrophy thus formed. 5 However, the pathogenic role of Ang II-independent constitu...

Notch signaling is involved in an intercellular communication mechanism that is essential for coordinated cell fate determination and tissue morphogenesis. The biological effects of Notch signaling are context-dependent. We investigated the functional and hierarchical relationship between angiotensin (Ang) II receptor signaling and Notch signaling in vascular smooth muscle cells (VSMCs). A fluorogenic substrate assay revealed directly that the enzymatic activity of γ-secretase was enhanced after 10 min of Ang II stimulation in HEK293 cells expressing Ang II type 1 receptor. Notch cleavage by γ-secretase was consistently induced and peaked at 10 min after Ang II stimulation, and the Ang II-stimulated increase in Notch intracellular domain production was significantly suppressed by treatment with the γ-secretase inhibitor DAPT. Treatment with DAPT also significantly reduced the Ang II-stimulated proliferation and migration of human aortic VSMCs, as revealed by BrdU incorporation and the Boyden chamber assay, respectively. Systemic administration of the γ-secretase inhibitor dibenzazepine reduced Ang II-induced medial thickening and perivascular fibrosis in the aortas of wild-type mice. These findings suggest that the hierarchical Ang II receptor-Notch signaling pathway promotes the proliferation and migration of VSMCs, and thereby contributes to the progression of vascular remodeling.