Excess aldosterone (ALDO) causes hypertension (HTN), and cardiac hypertrophy, injury and dysfunction. The role of HTN in ALDO-mediated cardiac injury remains controversial. Whether cardiac injury is blood pressure (BP)-dependent, -independent or exacerbated by HTN is not fully understood. We aim to study the role of BP in ALDO-mediated cardiac hypertrophy, inflammation and fibrosis.
Eight-week old uninephrectomized male Sprague Dawley rats (N=6/grp) were randomly assigned to the following 3 groups: Control, ALDO/SALT, ALDO/SALT+3-AHT (Triple Anti-Hypertensive Therapy). ALDO (0.75 μg/h) or vehicle (PEG 300) was administered by osmotic minipumps. SALT (1.0 % NaCl + 0.3 % KCl) was administered in tap water. 3-AHT (240 mg/kg hydralazine, 75 mg/kg hydrochlorothiazide, 15 mg/kg reserpine) was administered in the food. Another set of animals (N=6/grp) was implanted with radiotelemetry probes for BP monitoring. Left ventricle (LV) gene expression (GE) was quantified by qRT-PCR.
3-AHT reduced MAP (126 ± 4 vs. 178 ± 3 mm Hg, p<0.05 vs. ALDO, controls: 108 ± 1). 3-AHT attenuated cardiac (3.8 ± 0.1 vs. 4.0 ± 0.1 HW/BW, p<0.05 vs. ALDO; controls: 3.5 ± 0.1) and LV (2.8 ± 0.1 vs. 3.0 ± 0.1 LVW/BW, p<0.05 vs. ALDO; controls: 2.4 ± 0.1) hypertrophy. 3-AHT abolished ALDO-mediated LV GE upregulation of fibrosis (collagen I, collagen III, fibronectin, Timp1, periostin) and inflammation (osteopontin, MCP-1, TGFβ, Hmox1) markers. A similar effect was observed with novel LV ALDO-target genes such as Reg3b, collagen VIII, Prss35, Ltbp2 or Pcp4. 3-AHT drug administration in the food caused no change in NaCl intake. However, to avoid the confounding effect of the natriuretic drug hydrochlorothiazide, a group of animals was treated with hydralazine and reserpine alone (2-AHT). 2-AHT treatment attenuated HTN (135 ± 4 vs. 178 ± 3 mm Hg, p<0.05 vs. ALDO) but did not modify ALDO-mediated cardiac or LV hypertrophy. However, 2-AHT also abolished ALDO-mediated GE upregulation of fibrosis and inflammation markers, as well as novel LV ALDO-target genes.
These results suggest that ALDO-mediated LV GE regulation in vivo is BP-dependent without excluding that ALDO may exacerbate the HTN-mediated cardiac injury. A stricter BP management may benefit patients with elevated ALDO levels.