Cardiovascular disease is a major cause of death worldwide. Inflammasome infiltration has been identified to play a central role in the pathological progression of certain cardiovascular diseases, such as vascular damage spanning atherosclerosis, aneurysm, or arteritis; ischemic heart disease; and other nonischemic heart diseases including diabetic cardiomyopathy, chronic heart failure, and hypertension- or virus-induced cardiac dysfunction. The NLRP3 inflammasome, a key participant in the innate immune response, requires both priming and activation signals for the initiation of inflammation. Piling evidence has revealed that the NLRP3 inflammasome could exert an inflammatory effect by inducing the secretion of proinflammatory cytokines (i.e., IL-1β, IL-18) or could cause pyroptosis, a novel programmed cell death process, in a caspase-1-dependent manner. The importance of the NLRP3 inflammasome in cardiac disease has been broadly investigated. In this review, we present the current knowledge regarding the function of NLRP in vascular disease, ischemic heart disease, and nonischemic heart disease and discuss the potential therapeutic options targeting the NLRP3 inflammasome.

Oxidative stress-induced endothelial dysfunction plays a key role in ischemia/reperfusion injury. Recent evidence indicates that endothelial progenitor cell-derived microvesicles (EPC-MVs) can promote angiogenesis of endothelial cells (ECs). Here, we investigated the potential effects of EPC-MVs on hypoxia/reoxygenation (H/R) injury in human brain microvascular ECs (hb-ECs). MVs were prepared from EPCs cultured in a serum deprivation (SD) medium (starving stress, sEPC-MVs) or SD medium containing tumor necrosis factor-α(TNFα) (apoptotic stress, aEPC-MVs). H/R injury model of hb-ECs was produced by 6 hr hypoxia (1% O₂) and 24 hr reoxygenation. The H/R hb-ECs were co-cultured with EPC-MVs. Results showed that (1) H/R hb-ECs were dysfunctional and coupled with increased apoptosis and ROS overproduction; (2) under two different conditions, EPCs displayed remarkable difference in caspase 3 and miR126 expression, which were carried by the corresponsive EPC-MVs; (3) functionally, sEPC-MVs had beneficial effects on H/R hb-ECs, whereas aEPC-MVs had detrimental effects; (4) the diverse effects of sEPC-MVs and aEPC-MVs were associated with the changes in miR126 and eNOS expression and were abolished by PI3K inhibitor. In conclusion, sEPCs-MVs and aEPC-MVs are functionally different on hb-EC apoptosis and dysfunction via their carried RNAs associated with ROS production and PI3K/eNOS/NO pathway.

Summary: Endothelial progenitor cells (EPCs), which can be cultured in vitro from mononuclear cells in peripheral blood or bone marrow, express both hematopoietic stem cell and endothelial cell markers on their surface. They are believed to participate in endothelial repair and postnatal angiogenesis due to their abilities of differentiating into endothelial cells and secreting protective cytokines and growth factors. Mounting evidence suggests that circulating EPCs are reduced and dysfunctional in various diseases including hypertension, diabetes, coronary heart disease, and ischemic stroke. Therefore, EPCs have been documented to be a potential biomarker for vascular diseases and a hopeful candidate for regenerative medicine. Ischemic stroke, as the major cause of disability and death, still has limited therapeutics based on the approaches of vascular recanalization or neuronal protection. Emerging evidence indicates that transplantation of EPCs is beneficial for the recovery of ischemic cerebral injury. EPC‐based therapy could open a new avenue for ischemic cerebrovascular disease. Currently, clinical trials for evaluating EPC transfusion in treating ischemic stroke are underway. In this review, we summarize the general conceptions and the characteristics of EPCs, and highlight the recent research developments on EPCs. More importantly, the rationale, perspectives, and strategies for using them to treat ischemic stroke will be discussed.

Angiotensin-converting enzyme 2 (ACE2) is a lately discovered enzyme catalyzing Angiotensin II into Angiotensin 1-7. Angiotensin II has been reported to impair endothelial progenitor cell (EPC) function and is detrimental to stroke. Here, we studied the role of ACE2 in regulating EPC function in vitro and in vivo. EPCs were cultured from human renin and angiotensinogen transgenic (R+A+) mice and their controls (R−A−). In in vitro experiments, EPCs were transduced with lentivirus-ACE2 or lentivirus-green fluorescence protein. The effects of ACE2 overexpression on EPC function and endothelial NO synthase (eNOS)/nicotinamide adenine dinucleotide phosphate oxidase (Nox) expression were determined. ACE2, eNOS, and Nox inhibitors were used for pathway validation. In in vivo studies, the therapeutic efficacy of EPCs overexpressing ACE2 was determined at day 7 after ischemic stroke induced by middle cerebral artery occlusion. We found that (1) lentivirus-ACE2 transduction resulted in a 4-fold increase of ACE2 expression in EPCs. This was accompanied with an increase in eNOS expression and NO production, and a decrease in Nox2 and -4 expression and reactive oxygen species production. (2) ACE2 overexpression improved the abilities of EPC migration and tube formation, which were impaired in R+A+ mice. These effects were inhibited by ACE2 or eNOS inhibitor and further enhanced by Nox inhibitor. (3) Transfusion of lentivirus-ACE2–primed EPCs reduced cerebral infarct volume and neurological deficits, and increased cerebral microvascular density and angiogenesis. Our data demonstrate that ACE2 improves EPC function, via regulating eNOS and Nox pathways, and enhances the efficacy of EPC-based therapy for ischemic stroke.