Aldosterone Increases Early Atherosclerosis and Promotes Plaque Inflammation Through a Placental Growth Factor‐Dependent Mechanism

Abstract

BackgroundAldosterone levels correlate with the incidence of myocardial infarction and mortality in cardiovascular patients. Aldosterone promotes atherosclerosis in animal models, but the mechanisms are poorly understood.Methods and ResultsAldosterone was infused to achieve pathologically relevant levels that did not increase blood pressure in the atherosclerosis‐prone apolipoprotein E–knockout mouse (ApoE−/−). Aldosterone increased atherosclerosis in the aortic root 1.8±0.1‐fold after 4 weeks and in the aortic arch 3.7±0.2‐fold after 8 weeks, without significantly affecting plaque size in the abdominal aorta or traditional cardiac risk factors. Aldosterone treatment increased lipid content of plaques (2.1±0.2‐fold) and inflammatory cell content (2.2±0.3‐fold), induced early T‐cell (2.9±0.3‐fold) and monocyte (2.3±0.3‐fold) infiltration into atherosclerosis‐prone vascular regions, and enhanced systemic inflammation with increased spleen weight (1.52±0.06‐fold) and the circulating cytokine RANTES (regulated and normal T cell secreted; 1.6±0.1‐fold). To explore the mechanism, 7 genes were examined for aldosterone regulation in the ApoE−/− aorta. Further studies focused on the proinflammatory placental growth factor (PlGF), which was released from aldosterone‐treated ApoE−/− vessels. Activation of the mineralocorticoid receptor by aldosterone in human coronary artery smooth muscle cells (SMCs) caused the release of factors that promote monocyte chemotaxis, which was inhibited by blocking monocyte PlGF receptors. Furthermore, PlGF‐deficient ApoE−/− mice were resistant to early aldosterone‐induced increases in plaque burden and inflammation.ConclusionsAldosterone increases early atherosclerosis in regions of turbulent blood flow and promotes an inflammatory plaque phenotype that is associated with rupture in humans. The mechanism may involve SMC release of soluble factors that recruit activated leukocytes to the vessel wall via PlGF signaling. These findings identify a novel mechanism and potential treatment target for aldosterone‐induced ischemia in humans.

Endothelial mineralocorticoid receptor contributes to systolic dysfunction induced by pressure overload without modulating cardiac hypertrophy or inflammation

“…2013) and atherosclerosis (McGraw et al. 2013). We have previously reported that MR activation by aldosterone upregulates ICAM‐1 in human coronary ECs (Caprio et al.…”

“…2008) and that this process contributes to aldosterone‐induced vascular inflammation and atherosclerosis in vivo (McGraw et al. 2013; Marzolla et al. 2017).…”

“…We hypothesized that EC‐MR contributes to adverse cardiac remodeling and HF by enhancing proinflammatory leukocyte recruitment in the LV and cardiac inflammation as it does in the vasculature (McGraw et al. 2013). To test this hypothesis, we subjected mice with MR specifically deleted from ECs (EC‐MR −/−) , but intact in leukocytes, to TAC and compared the cardiac response to their EC‐MR‐intact littermates (EC‐MR +/+ ).…”

Assessment of turbulent flow effects on the vessel wall using four-dimensional flow MRI

“…Of particular interest as disease predictors and descriptors are areas of turbulent flow and their effects on the vessel walls. Turbulent flow near the vessel wall has been associated with adverse vascular remodelling, and damage to the vessel wall (3)(4)(5)(6)(7)(8)(9)(10)). …”

Placental expression of the angiogenic placental growth factor is stimulated by both aldosterone and simulated starvation

“…Organ fibrosis and atherosclerosis are promoted by excess aldosterone (10). Upon exposure of vessels to aldosterone in models of atherosclerosis, enhanced placental growth factor (PlGF) expression has been observed, mediated by a mineralocorticoid responsive element in the promoter region of plgf (10,11).…”