Abstract
Activation of aldosterone/mineralocorticoid receptors (MR) has been implicated in vascular dysfunction of diabetes. Underlying mechanisms are elusive. Therefore, we investigated the role of Rho kinase (ROCK) in aldosterone/MR signaling and vascular dysfunction in a model of diabetes. Diabetic obese mice (db/db) and control counterparts (db/+) were treated with MR antagonist (MRA, potassium canrenoate, 30 mg/kg/day, 4 weeks) or ROCK inhibitor, fasudil (30 mg/kg/day, 3 weeks). Plasma aldosterone was increased in db/db versus db/+. This was associated with enhanced vascular MR signaling. Norepinephrine (NE)-induced contraction was increased in arteries from db/db mice. These responses were attenuated in mice treated with canrenoate or fasudil. Db/db mice displayed hypertrophic remodeling and increased arterial stiffness, improved by MR blockade. Vascular calcium sensitivity was similar between depolarized arteries from db/+ and db/db. Vascular hypercontractility in db/db mice was associated with increased myosin light chain phosphorylation and reduced expression of PKG-1α. Vascular RhoA/ROCK signaling and expression of pro-inflammatory and pro-fibrotic markers were exaggerated in db/db mice, effects that were attenuated by MRA. Fasudil, but not MRA, improved vascular insulin sensitivity in db/db mice, evidenced by normalization of Irs1 phosphorylation. Our data identify novel pathways involving MR-RhoA/ROCK-PKG-1 that underlie vascular dysfunction and injury in diabetic mice.
Highlights
The high mortality and morbidity rates worldwide associated with obesity-related type 2 diabetes are attributed, in large part, to cardiovascular complications
We previously demonstrated an important role for aldosterone/mineralocorticoid receptor (MR) in vascular damage and metabolic derangement in obesity-associated diabetes[5,6,7,10] and others have shown a role for ROCK in endothelial
(A) Pro-fibrotic markers such as Col1a, Col3a and Tgfb[1] mRNA levels were increased in mesenteric arteries from db/db compared to db/+ mice. (B) Pro-inflammatory markers such as IL-6, Tnfa and Mcp-1 mRNA levels were increased in mesenteric arteries from db/db compared to db/+ mice
Summary
The high mortality and morbidity rates worldwide associated with obesity-related type 2 diabetes are attributed, in large part, to cardiovascular complications. We and others demonstrated that aldosterone, through mineralocorticoid receptor (MR) activation, is involved in the regulation of structural and functional vascular changes, in particular in endothelial dysfunction and vascular hypercontractility, often associated with obesity-related type 2 diabetes and hypertension. Activation of the RhoA/ROCK signaling pathway plays an important role in enhanced vascular tone in hypertension[11,12,13], and in cellular metabolic processes, including insulin resistance[14,15,16,17,18]. It can be surmised that the RhoA/ROCK pathway constitutes a potential point of cross-talk linking metabolic and hemodynamic abnormalities with insulin resistance and obesity. The role of ROCK as an effector of aldosterone/MR activation in vascular injury in obesity-associated diabetes is unknown and was the focus of our study
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