Abstract

Objective: Elevated levels of the hormone aldosterone are associated with increased risk of myocardial infarction and stroke in humans and increased progression and inflammation of atherosclerotic plaques in animal models. Aldosterone acts through the mineralocorticoid receptor (MR) which is expressed in vascular smooth muscle cells (SMCs) where it promotes SMC calcification and chemokine secretion in vitro. The objective of this study is to explore the role of the MR specifically in SMCs in the progression of atherosclerosis and the associated vascular inflammation in vivo in the apolipoprotein E knockout (ApoE−/−) mouse model.Methods and Results: Male ApoE−/− mice were bred with mice in which MR could be deleted specifically from SMCs by tamoxifen injection. The resulting atheroprone SMC-MR-KO mice were compared to their MR-Intact littermates after high fat diet (HFD) feeding for 8 or 16 weeks or normal diet for 12 months. Body weight, tail cuff blood pressure, heart and spleen weight, and serum levels of glucose, cholesterol, and aldosterone were measured for all mice at the end of the treatment period. Serial histologic sections of the aortic root were stained with Oil Red O to assess plaque size, lipid content, and necrotic core area; with PicroSirius Red for quantification of collagen content; by immunofluorescent staining with anti-Mac2/Galectin-3 and anti-smooth muscle α-actin antibodies to assess inflammation and SMC marker expression; and with Von Kossa stain to detect plaque calcification. In the 16-week HFD study, these analyses were also performed in sections from the brachiocephalic artery. Flow cytometry of cell suspensions derived from the aortic arch was also performed to quantify vascular inflammation after 8 and 16 weeks of HFD. Deletion of the MR specifically from SMCs did not significantly change plaque size, lipid content, necrotic core, collagen content, inflammatory staining, actin staining, or calcification, nor were there differences in the extent of vascular inflammation between MR-Intact and SMC-MR-KO mice in the three experiments.Conclusion: SMC-MR does not directly contribute to the formation, progression, or inflammation of atherosclerotic plaques in the ApoE−/− mouse model of atherosclerosis. This indicates that the MR in non-SMCs mediates the pro-atherogenic effects of MR activation.

Highlights

  • The majority of myocardial infarctions and ischemic strokes are caused by rupture and thrombosis of atherosclerotic plaques, making atherosclerosis the leading cause of death worldwide [1, 2]

  • We developed an atheroprone mouse model in which the mineralocorticoid receptor (MR) can be deleted from smooth muscle cells (SMCs) in an inducible fashion in order to investigate the hypothesis that SMC-MR contributes to the development and progression of atherosclerosis and promotes vascular inflammation

  • In order to explore the role of SMC-MR in atherosclerosis, a well validated inducible SMC-specific MR knockout mouse [20, 24] was crossed to the atheroprone ApoE−/− background

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Summary

Introduction

The majority of myocardial infarctions and ischemic strokes are caused by rupture and thrombosis of atherosclerotic plaques, making atherosclerosis the leading cause of death worldwide [1, 2]. Ample clinical data reveal that elevated levels of the hormone aldosterone are associated with an increased risk of myocardial infarction and stroke [3,4,5]. The increased risk of cardiovascular ischemia with elevated aldosterone appears to be independent of blood pressure [3, 5], supporting a potential pro-atherosclerotic role for extra-renal MR. Preclinical studies using animal models of atherosclerosis to explore this phenomenon have demonstrated that administration of aldosterone to apolipoprotein E knockout (ApoE−/−) mice accelerates atherosclerosis and plaque inflammation [6, 7]. Pharmacologic MR blockade attenuates plaque development and inflammation in mouse [8,9,10], rabbit [11], and non-human primate models of atherosclerosis [12] through unknown mechanisms

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