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Steroidogenic acute regulatory protein/aldosterone synthase mediates angiotensin II-induced cardiac fibrosis and hypertrophy

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Abstract

Aldosterone produced in adrenal glands by angiotensin II (Ang II) is known to elicit myocardial fibrosis and hypertrophy. 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. Sprague–Dawley rats were randomized to following groups: Ang II infusion for a 4-week period, treatment with telmisartan, spironolactone or adrenalectomy during Ang II infusion. Sham-operated rats served as control. Relative to Sham rats, Ang II infusion significantly increased the protein levels of AT1 receptor, StAR, AS and their tissue expression in the adrenal glands and heart. In coincidence with reduced aldosterone level in the heart, telmisartan, an AT1 receptor blocker, significantly down-regulated the protein level and expression of StAR and AS. Ang II induced changes in the expression of AT1/StAR/AS were not altered by an aldosterone receptor antagonist spironolactone. Furthermore, Ang II augmented migration of macrophages, protein level of TGFβ1, phosphorylation of Smad2/3 and proliferation of myofibroblasts, accompanied by enhanced perivascular/interstitial collagen deposition and cardiomyocyte hypertrophy, which all were significantly abrogated by telmisartan or spironolactone. However, adrenalectomy did not fully suppress Ang II-induced cell migration/proliferation and fibrosis/hypertrophy, indicating a role of aldosterone synthesized within the heart in pathogenesis of Ang II induced injury. These results indicate that myocardial fibrosis and hypertrophy stimulated by Ang II is associated with tissue-specific activation of aldosterone synthesis, primarily mediated by AT1/StAR/AS signaling pathways.

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Correspondence to Zhi-Qing Zhao.

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Zhang, W., Zheng, R., Bai, F. et al. Steroidogenic acute regulatory protein/aldosterone synthase mediates angiotensin II-induced cardiac fibrosis and hypertrophy. Mol Biol Rep 47, 1207–1222 (2020). https://doi.org/10.1007/s11033-019-05222-7

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Keywords

  • Angiotensin II
  • AT1 receptor
  • Aldosterone synthase
  • Cardiac fibrosis
  • Cardiac hypertrophy
  • Steroidogenic acute regulatory protein