Aldosterone mediates angiotensin II‐induced myocardial fibrosis and hypertrophy via steroidogenic acute regulatory protein and aldosterone synthase

Abstract

ObjectiveAldosterone produced in the adrenal glands through angiotensin II (Ang II) is known to elicit myocardial fibrosis and hypertrophy. The purpose of this study was designed to test the hypothesis that Ang II causes cardiac morphological changes through the steroidogenic acute regulatory protein (StAR)/aldosterone synthase (AS)‐dependent aldosterone synthesis primarily initiated in the heart.MethodsSprague‐Dawley rats were observed for a 28‐day period and randomized to the following groups: untreated Ang II infusion with osmotic pumps (500 ng/kg/min), dietary Ang II AT1 receptor blocker, telmisartan (10 mg/kg/day), dietary aldosterone receptor blocker, spironolactone (100 mg/kg/day) and adrenalectomy before Ang II infusion. Rats received saline infusion were served as the Sham controls.ResultsRelative to the Sham animals, Ang II infusion significantly increased protein levels including Ang II AT1 receptors, StAR and AS as well as their tissue expression in the adrenal glands and heart, as identified by Western blot assay and immunohistochemical staining. Administration of telmisartan, significantly down‐regulated the protein level and expression of StAR and AS, but these changes were not altered by treatment with spironolactone, suggesting that Ang II AT1 receptors are involved as an upstream regulator and the blockade of aldosterone receptor does not affect the AT1/StAR/AS signaling. Following activation of these signaling cascades, Ang II infusion further augmented migration of macrophages, protein level of TGFβ1, phosphorylation of Smad2/3 and proliferation of myofibroblasts, in coincidence with enhanced perivascular/interstitial collagen deposition and cardiomyocyte hypertrophy, which all were significantly abrogated by either telmisartan or spironolactone treatment (all P<0.05 vs. Ang II group). However, removing adrenal glands by adrenalectomy did not fully suppress Ang II‐induced cell migration/proliferation and fibrosis/hypertrophy, indicating a role of aldosterone synthesized within the heart in the pathogenesis of Ang II induced cardiac injury.ConclusionsMyocardial fibrosis and hypertrophy stimulated by Ang II is associated with tissue‐specific activation of aldosterone synthesis, which are primarily mediated via AT1/StAR/AS signaling pathways. Understanding these maladaptive responses to Ang II could lead to the development of novel therapeutic strategy.Support or Funding InformationThis study was supported in part by grants from the Mercer University School of Medicine, the Medcen Community Health Foundation, Georgia and the National Natural Science Foundation of China (81470436).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.