Low-Dose Mineralocorticoid Receptor Blockade Prevents Western Diet–Induced Arterial Stiffening in Female Mice

Abstract

Women are especially predisposed to development of arterial stiffening secondary to obesity due to consumption of excessive calories. Enhanced activation of vascular mineralocorticoid receptors impairs insulin signaling, induces oxidative stress, inflammation and maladaptive immune responses. We tested whether a sub-pressor dose of mineralocorticoid receptor antagonist, spironolactone (1 mg•kg−1•day−1) prevents aortic and femoral artery stiffening in female C57BL/6J mice fed a high fat/high sugar western diet (WD) for four months (i.e., from 4–20 weeks of age). Aortic and femoral artery stiffness were assessed using ultrasound, pressurized vessel preparations and atomic force microscopy. WD induced weight gain and insulin resistance compared to control diet-fed mice and these abnormalities were unaffected by spironolactone. Blood pressures and heart rates were normal and unaffected by diet or spironolactone. Spironolactone prevented WD-induced stiffening of aorta and femoral artery as well as endothelial and vascular smooth muscle cells within aortic explants. Spironolactone prevented WD-induced impaired aortic protein kinase B/endothelial nitric oxide synthase signaling, as well as, impaired endothelium-dependent and –independent vasodilation. Spironolactone ameliorated WD-induced aortic medial thickening and fibrosis and the associated activation of the pro-growth extracellular receptor kinase 1/2 pathway. Finally, preservation of normal arterial stiffness with spironolactone in WD-fed mice was associated with attenuated systemic and vascular inflammation and an anti-inflammatory shift in vascular immune cell marker genes. Low-dose spironolactone may represent a novel prevention strategy to attenuate vascular inflammation, oxidative stress, and growth pathway signaling and remodeling to prevent development of arterial stiffening secondary to consumption of a WD.

Vascular Mineralocorticoid Receptors

“…28 Similar results were obtained in wild-type mice that received high-fat diet. 5 In line with this, high-fat diet-induced endothelial dysfunction and impaired vascular relaxation was restored by endothelial MR deletion. 1,6 This was accompanied by reduced oxidative stress and improved nitric oxide production in EC-MRKO mice 1,6 or after spironolactone treatment.…”

“…1,6 This was accompanied by reduced oxidative stress and improved nitric oxide production in EC-MRKO mice 1,6 or after spironolactone treatment. 5 It has been demonstrated that ENaC is also expressed outside of the kidney in endothelial cells and contributes to endothelial cell and vascular stiffness. 29,30 ENaC expression increases with age or in response to high-fat diet.…”

Sex‐Specific Mechanisms of Resistance Vessel Endothelial Dysfunction Induced by Cardiometabolic Risk Factors

“…In a mouse model of Western diet‐induced obesity, females developed higher plasma aldosterone levels compared with males 25. MR blockade in rodents improved endothelial function in females more than males in the setting of diabetes mellitus or hyperleptinemia—common complications of obesity 26, 27. These studies support a potential role for MR in endothelial dysfunction induced by cardiometabolic risk factors and suggest that the role of MR may be enhanced in females.…”

Angiotensin 1–7 Is a Negative Modulator of Aldosterone Secretion In Vitro and In Vivo

“…Because aldosterone excess per-se has been linked to multiple potential unfavorable sequels, such as the evolution of hypertension, 25 cardiac and vascular fibrosis, 26,27 insulin resistance, 28 and worse prognosis after myocardial infarction, 29 the present report should instigate further studies of whether/how this previously unrecognized inhibitor of aldosterone secretion can be used under conditions in which high circulating aldosterone is a likely contributor to disease.…”