Cardiac Specific Increase in Aldosterone Production Induces Coronary Dysfunction in Aldosterone Synthase–Transgenic Mice

Abstract

Background-Elevated circulating aldosterone level is associated with impaired cardiovascular function. Although the mechanisms are not fully understood, aldosterone antagonists decrease total and cardiovascular mortality in heart failure and myocardial infarction. Aldosterone induces cardiac fibrosis in experimental models, and it is synthesized locally in rat heart. These observations suggest pathological effects of aldosterone in heart that remain unclear. Methods and Results-Transgenic mice (TG) that overexpress the terminal enzyme of aldosterone biosynthesis, aldosterone synthase (AS), in heart have been raised by gene targeting with the ␣-myosin heavy chain promoter. AS mRNA increased 100-fold and aldosterone concentration 1.7-fold in hearts of male TG mice relative to wild-type. No structural or myocardial alterations were evidenced, because ventricle/body weight, AT 1 and AT 2 receptor binding, and collagen content were unchanged in TG. No alteration in cardiac function was evidenced by echocardiography, isolated perfused heart, or whole-cell patch clamp experiments. In contrast, coronary function was impaired, because basal coronary flow was decreased in isolated perfused heart (Ϫ55% of baseline values), and vasodilatation to acetylcholine, bradykinin, and sodium nitroprusside was decreased by 75%, 60%, and 75%, respectively, in TG mice compared with wild-type, showing that the defect was not related to NO production. Conclusions-Increased cardiac aldosterone production in male mice induces a major coronary endothelium-independent dysfunction with no detectable alterations in cardiac structure and function. However, coronary dysfunction may be harmful for coronary adaptation to increased flow demand.

From aldosteronism to oxidative stress: the role of excessive intracellular calcium accumulation

“…29 The upregulation of ALDO synthase in the heart accounts for increased tissue levels of ALDO, but are not accompanied by fibrosis. 30 Thus, the evidence gathered to date indicates the adverse myocardial remodeling during ALDOST is both independent of hypertension and unrelated to plasma-or tissue-derived ALDO per se. Therefore, some other circulating factor that accompanies aldosteronism must be operative (vide infra).…”

Effects of Aldosterone on the Vasculature

“…Garnier et al 24 overexpressed aldosterone synthase in the heart, with a 1.7-fold increase in myocardial aldosterone concentration, which was associated with endothelium-dependent and -independent coronary artery dysfunction without vascular inflammation or myocardial fibrosis. Impaired vascular function may be the first manifestation of aldosterone-induced cardiovascular damage.…”

Critical Role of Apoptosis Signal-Regulating Kinase 1 in Aldosterone/Salt-Induced Cardiac Inflammation and Fibrosis

“…6,21,22 Both strains of mice were divided into 3 groups, including the following: (1) saline infusion (control); (2) aldosterone infusion; and (3) aldosterone infusion plus 0.3% KCl supplementation. Aldosterone (Sigma; 0.2 mg/kg per day) dissolved in 5% ethanol or saline alone as the control was infused continuously into both strains via osmotic minipumps (model 1002, Alzet Durect Corp) for 4 weeks.…”