Abstract 254: A Novel Mechanism for Aberrant Aldosterone Production in Heart Failure

Objective: Aldosterone production by the adrenal gland is mainly regulated by the renin-angiotensin system (RAS), which is normally suppressed by a high-salt diet. However, plasma aldosterone levels are elevated in proportion to the severity of heart failure even if caused by high-salt intake. The inappropriate increase in plasma aldosterone level could not be diminished by pharmacological blockade of the RAS. We investigated the cellular mechanism underlying the aberrant aldosterone production in heart failure beyond the activation of RAS. Methods and Results: Dahl-salt sensitive rats fed high salt diet developed malignant hypertension, resulting in heart failure with increased plasma aldosterone level. The gene expression pattern of the adrenal gland from heart failure rats showed strikingly upregulated β3-adrenergic receptor (β3-AR) expression. Immunohistochemical staining confirmed that heart failure increased β3-AR expression in zona glomerulosa cells in adrenal gland of Dahl-salt sensitive rats. And the staining of pimonidazole, a hypoxia probe, revealed that the outer layer of adrenal cortex in the heart failure rat was under hypoxic condition. Hypoxia and DMOG, a chemical stabilizer of hypoxia-inducible factor, strongly induced β3-AR mRNA expression in H295R human adrenocortical carcinoma cells. Hypoxia-reoxygenation stimuli induced aldosterone production from H295R cells, which was blocked by SR59230A, a selective β3-AR antagonist, but not by losartan, an angiotensin II receptor blocker (ARB). Hypoxia endowed catecholamine responsiveness in H295R cells by increased β3-AR expression, wherein β3-AR agonist increased the phosphorylation levels of hormone-sensitive lipase (HSL) through activation of ERK pathway. Conclusions: In the present study, we demonstrated that the β3-AR induction in adrenal gland by hypoxia played an important role in aberrant aldosterone production in heart failure. The catecholamine stimuli through β3-AR in adrenocortical cells caused the ERK-mediated phosphorylation of HSL, suggesting that the HSL promotes lipolysis to supply substrates for the aldosterone biosynthesis.