Aldosterone is a mineralocorticoid hormone that controls body fluid and electrolyte balance. Excess aldosterone is associated with cardiovascular and metabolic diseases. Inflammation plays a critical role on vascular damage promoted by aldosterone and aggravates vascular abnormalities, including endothelial dysfunction, vascular remodeling, fibrosis and oxidative stress, and other manifestations of end-organ damage that are associated with hypertension, other forms of cardiovascular disease, and diabetes mellitus and the metabolic syndrome. Over the past few years, many studies have consistently shown that aldosterone activates cells of the innate and adaptive immune systems. Macrophages and T cells accumulate in the kidneys, heart, and vasculature in response to aldosterone, and infiltration of immune cells contributes to end-organ damage in cardiovascular and metabolic diseases. Aldosterone activates various subsets of innate immune cells such as dendritic cells and monocytes/macrophages, as well as adaptive immune cells such as T lymphocytes, and, by activation of mineralocorticoid receptors stimulates proinflammatory transcription factors and the production of adhesion molecules and inflammatory cytokines and chemokines. This review will briefly highlight some of the studies on the involvement of aldosterone in activation of innate and adaptive immune cells and its impact on the cardiovascular system. Since aldosterone plays a key role in many cardiovascular and metabolic diseases, these data will open up promising perspectives for the identification of novel biomarkers and therapeutic targets for prevention and treatment of diseases associated with increased levels of aldosterone, such as arterial hypertension, obesity, the metabolic syndrome, and heart failure.

Aldosterone excess aggravates endothelial dysfunction in diabetes and hypertension by promoting the increased generation of reactive oxygen species, inflammation, and insulin resistance. Aldosterone activates the molecular platform inflammasome in immune system cells and contributes to vascular dysfunction induced by the mineralocorticoid hormone. It is unclear as to whether the NLRP3 inflammasome associated with the mineralocorticoid receptor contributes to vascular dysfunction in diabetic conditions. Here, we tested the hypothesis that an excess of aldosterone induces vascular dysfunction in type 2 diabetes, via the activation of mineralocorticoid receptors (MR) and assembly of the NLRP3 inflammasome. Mesenteric resistance arteries from control (db/m) and diabetic (db/db) mice treated with vehicle, spironolactone (MR antagonist) or an NLRP3 selective inhibitor (MCC950) were used to determine whether NLRP3 contributes to diabetes-associated vascular dysfunction. Db/db mice exhibited increased vascular expression/activation of caspase-1 and IL-1β, increased plasma IL-1β levels, active caspase-1 in peritoneal macrophages, and reduced acetylcholine (ACh) vasodilation, compared to db/m mice. Treatment of db/db mice with spironolactone and MCC950 decreased plasma IL-1β and partly restored ACh vasodilation. Spironolactone also reduced active caspase-1-positive macrophages in db/db mice, events that contribute to diabetes-associated vascular changes. These data clearly indicate that MR and NLRP3 activation contribute to diabetes-associated vascular dysfunction and pro-inflammatory phenotype.

NADPH oxidase (NOX) 1 but not NOX4-dependent oxidative stress plays a role in diabetic vascular disease, including atherosclerosis. Endothelin (ET)-1 has been implicated in diabetes-induced vascular complications. We showed that crossing mice overexpressing human ET-1 selectively in endothelium (eET-1) with apolipoprotein E knockout (Apoe^−/−) mice enhanced high-fat diet-induced atherosclerosis in part by increasing oxidative stress. We tested the hypothesis that ET-1 overexpression in the endothelium would worsen atherosclerosis in type 1 diabetes through a mechanism involving NOX1 but not NOX4. Six-week-old male Apoe^−/− and eET-1/Apoe^−/− mice with or without Nox1 (Nox1^−/y) or Nox4 knockout (Nox4^−/−) were injected intraperitoneally with either vehicle or streptozotocin (55 mg/kg/day) for 5 days to induce type 1 diabetes and were studied 14 weeks later. ET-1 overexpression increased 2.5-fold and five-fold the atherosclerotic lesion area in the aortic sinus and arch of diabetic Apoe^−/− mice, respectively. Deletion of Nox1 reduced aortic arch plaque size by 60%; in contrast, Nox4 knockout increased lesion size by 1.5-fold. ET-1 overexpression decreased aortic sinus and arch plaque alpha smooth muscle cell content by ∼35% and ∼50%, respectively, which was blunted by Nox1 but not Nox4 knockout. Reactive oxygen species production was increased two-fold in aortic arch perivascular fat of diabetic eET-1/Apoe^−/− and eET-1/Apoe^−/−/Nox4^−/− mice but not eET-1/Apoe^−/−/Nox1^y/− mice. ET-1 overexpression enhanced monocyte/macrophage and CD3⁺ T-cell infiltration ∼2.7-fold in the aortic arch perivascular fat of diabetic Apoe^−/− mice. Both Nox1 and Nox4 knockout blunted CD3⁺ T-cell infiltration whereas only Nox1 knockout prevented the monocyte/macrophage infiltration in diabetic eET-1/Apoe^−/− mice. Endothelium ET-1 overexpression enhances the progression of atherosclerosis in type 1 diabetes, perivascular oxidative stress, and inflammation through NOX1.

Objective: Extracellular ATP is elevated in hypertensive mice and humans and may trigger immune activation through the purinergic receptor P2X7 (P2RX7) causing interleukin-1β production and T-cell activation and memory T-cell development. Furthermore, P2RX7 single nucleotide polymorphisms (SNP) are associated with hypertension. We hypothesized that P2RX7 activation contributes to hypertension and cardiovascular injury by promoting immune activation. Methods: Male wild-type and P2rx7 ^–/– mice were infused or not with angiotensin II (AngII) for 14 days. A second group of AngII-infused wild-type mice were co-infused with the P2RX7 antagonist AZ10606120 or vehicle. BP was monitored by telemetry. Cardiac and mesenteric artery function and remodeling were assessed using ultrasound and pressure myography, respectively. T cells were profiled in thoracic aorta/perivascular adipose tissue by flow cytometry. Associations between SNPs within 50 kb of P2RX7 transcription, and BP or hypertension were modeled in 384 653 UK Biobank participants. Results: P2rx7 inactivation attenuated AngII-induced SBP elevation, and mesenteric artery dysfunction and remodeling. This was associated with decreased perivascular infiltration of activated and effector memory T-cell subsets. Surprisingly, P2rx7 knockout exaggerated AngII-induced cardiac dysfunction and remodeling. Treatment with a P2RX7 antagonist reduced BP elevation, preserved mesenteric artery function and reduced activated and effector memory T cell perivascular infiltration without adversely affecting cardiac function and remodeling in AngII-infused mice. Three P2RX7 SNPs were associated with increased odds of DBP elevation. Conclusion: P2RX7 may represent a target for attenuating BP elevation and associated vascular damage by decreasing immune activation.

Introduction: The emergence of the global COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus, SARS-CoV-2, has created a substantial burden on healthcare systems worldwide. The systemic impacts of COVID-19 infection are severe and broad in their implications, and the cardiovascular system is no exception. Discussion: Patients with a history of cardiovascular disease are at an increased risk for hospitalization and mortality, and COVID-19 infection has now been demonstrated to initiate acute, but serious, episodes of cardiovascular events such as stroke. Considering the rapid spread of COVID-19 across the globe and the inability of healthcare systems to address and adequately respond to the pandemic, therein lies an increased need for understanding the interplay between COVID-19 infection and cardiovascular disease. SARS-CoV-2 relies on binding the angiotensin-converting enzyme-2 (ACE2) receptor to infect host cells, with ACE2 representing a critical regulator of blood pressure homeostasis and proper cardiovascular functioning. Conclusion: Identifying the exact role of ACE2 in COVID-19 infection will have major implications for understanding the disease; therefore, here we have reviewed ACE2’s involvement in the pathogenesis of COVID-19 infection and the resulting end-organ damage. In addition, we have summarized how COVID-19 affects cardiovascular physiology, and how COVID-19 infection can manifest in acute cardiovascular events. Finally, we examine why patients with cardiovascular disease are at an increased risk of succumbing to COVID-19 and what the long-term cardiovascular implications of COVID-19 infection could mean. Relevance: This paper discusses the cardiovascular consequences of the global COVID-19 pandemic.