Abstract 011: TRPM7 is Cardiovascular Protective in Aldosterone-Induced Hypertension

Abstract

TRPM7 is a chanzyme that influences cellular Mg 2+ homeostasis and vascular signaling. We demonstrated that aldosterone mediates cellular effects through TRPM7-dependent signaling pathways. Since hyperaldosteronism causes hypertension and Mg 2+ wasting, we questioned whether TRPM7 plays a role in aldosterone-induced hypertension. Wild-type (WT) and TRPM7-deficient (M7+/Δ) mice were treated with aldosterone (600μg/Kg/day) and/or 1% NaCl (drinking water) (aldo, salt or aldo/salt) for 4 weeks. Blood pressure (BP) was evaluated by tail-cuff. Vessel function was investigated in mesenteric arteries by wire and pressure myography. Protein expression was assessed by western-blot and histology. Cardiac fibroblasts (CF) were isolated from WT and M7+/Δ. M7+/Δ exhibited increased BP by aldo (140mmHg), salt (135mmHg) and aldo/salt (137mmHg) vs M7+/Δ-veh (117mmHg) (p<0.05), whereas in WT, BP was increased only by aldo/salt (134mmHg). All treatments induced endothelial dysfunction in M7+/Δ as observed in acetylcholine-relaxation curves [Emax % M7+/Δ: aldo (81±4), salt (69±4) and aldo/salt (75±3.0), p<0.05], whereas in WT, Emax % was reduced after aldo (68±4) and aldo/salt (80±3). Phenylephrine-contraction and SNP-relaxation curves were similar among groups. Pressure myography showed that in WT, aldo/salt increased wall/lumen ratio (83%) inducing eutrophic inward remodeling, whereas M7+/Δ-veh presented 62% reduction in cross-sectional area vs WT, which was increased by salt and aldo/salt, resulting in hypertrophic outward remodeling. Collagen was increased in aortas from M7+/Δ by aldo (31%) and aldo/salt (45%) and no changes in WT. Aldo/salt induced higher collagen deposition in hearts (68%) and kidneys (126%) from M7+/Δ vs WT. Hearts and kidneys from M7+/Δ veh exhibited increased α-SMA (2-fold) and p-Stat1 (1.5-fold), whereas tissues from WT exhibited 3-fold increase only after treatments. CF from M7+/Δ stimulated with aldosterone (100nM) showed increased activation of Stat1 (177%), Smad3 (300%) and reduced pStat3 (70%) vs WT, p<0.05. We define a novel protective role of TRPM7 in the cardiovascular system, which when downregulated, promotes increased blood pressure, vascular remodeling and cardiac fibrosis mediated by aldosterone and salt.