Cardiovascular Pharmacology of the NLRP3 Inflammasome No abstract available

NLRP3 Inflammasome in Acute Myocardial Infarction Abstract: Acute myocardial infarction (AMI) is associated with the induction of a sterile inflammatory response that leads to further injury. The NACHT, leucine-rich repeat, and pyrin domain–containing protein 3 (NLRP3) inflammasome is a macromolecular structure responsible for the inflammatory response to injury or infection. NLRP3 can sense intracellular danger signals, such as ischemia and extracellular or intracellular alarmins during tissue injury. The NLRP3 inflammasome is primed and triggered by locally released damage-associated molecular patterns and amplifies the inflammatory response and cell death through caspase-1 activation. Here, we examine the scientific evidence supporting a role for NLRP3 in AMI and the available strategies to inhibit the effects of the inflammasome. Our focus is on the beneficial effects seen in experimental models of AMI in preclinical animal models and the initial results of clinical trials.

Cell-Specific Roles of NLRP3 Inflammasome in Myocardial Infarction Abstract: An accumulating body of evidence indicates that NLRP3 inflammasome plays a crucial role in the pathophysiology of cardiovascular diseases, including atherosclerosis and acute myocardial infarction (MI). NLRP3 inflammasome is a multimeric protein complex that leads to activation of caspase-1, which further induces maturation of interleukin (IL)-1β and IL-18. Activated caspase-1 also induces a particular form of cell death called pyroptosis by the cleavage of gasdermin D. Our and other groups have shown that inhibition of the NLRP3 inflammasome attenuates the inflammatory response and ameliorates myocardial dysfunction and remodeling in animal models of acute MI. Interestingly, investigations have suggested that NLRP3 inflammasome has cell-specific roles in different cell types, such as inflammatory cells, cardiomyocytes, cardiac fibroblasts, and vascular endothelial cells, after acute MI. Moreover, the recent CANTOS trial showed that inhibition of IL-1β was efficacious in secondary prevention for cardiovascular events in patients with previous MI. These findings suggest that NLRP3 inflammasome may be a potential target for the prevention and therapy of MI. This review summarizes recent knowledge on NLRP3 inflammasome and focuses on its cell-specific roles in acute MI.

Role of Caspase 1 in Ischemia/Reperfusion Injury of the Myocardium Abstract: Acute occlusion of a coronary artery can result in myocardial infarction—a leading cause of premature death. Prompt restoration of blood flow to the myocardium can prevent excessive death of cardiomyocytes and improve clinical outcome. Although the major mechanism of cell death after reperfusion is necrosis, it is now recognized that many other cell death pathways may be involved in ischemia–reperfusion (I/R) injury. Pyroptosis is one such cell death pathway that is caspase-1–dependent and induced in response to cellular insult. The activated caspase-1 protease cleaves and activates specific cellular targets including gasdermin D and the proinflammatory cytokines interleukin-1β and interleukin-18. The N-terminal fragment of gasdermin D forms plasma membrane pores resulting in cytosolic leakage and cell rupture, releasing interleukin-1β and interleukin-18. Evidence suggests that inflammation induced by I/R through the pyroptotic pathway contributes to cardiomyocyte death, excessive scar formation, and poor ventricular remodeling. For this reason, there is growing interest in targeting components of the pyroptotic pathway as a means of reducing I/R injury.

Soy Isoflavones Inhibit Endothelial Cell Dysfunction and Prevent Cardiovascular Disease Abstract: Soybeans are among the most popular foods worldwide, and intake of soy-containing foods has been associated with many health benefits in part because of it structure similar to estrogen. Epidemiologic studies have demonstrated that soy consumption improves serum profiles of hypercholesterolemic patients. Several studies have also indicated an inverse relationship between the consumption of soy isoflavones and the incidence of cardiovascular diseases (CVD). Soy is a rich dietary source of isoflavones. The main soy isoflavones are daidzein and genistein; equol, another isoflavone and a major intestinal bacterial metabolite of daidzein, is generated by enterobacterial effects. Many isoflavones have antioxidative effects and anti-inflammatory actions, as well as induce nitric oxide production to maintain a healthy endothelium and prevent endothelial cell dysfunction. These effects may limit the development of atherosclerosis and CVD and restore healthy endothelial function in altered endothelia. Although the evidence supporting the benefits of soy isoflavones in CVD prevention continues to increase, the association between soy isoflavones and disease is not fully understood. This review summarized recent progress in identifying the preventive mechanisms of action of dietary soybean isoflavones on vascular endothelial cells. Furthermore, it describes the beneficial roles that these isoflavones may have on endothelial dysfunction-related atherosclerosis.

Impact of Postdischarge Bleeding on Long-Term Mortality in Percutaneous Coronary Intervention Patients Taking Oral Anticoagulants Abstract: Although postdischarge bleeding (PDB) is known to negatively affect long-term outcome in patients undergoing percutaneous coronary intervention (PCI) with antiplatelet therapy (APT), the prognostic importance of PDB in patients who require both oral anticoagulants (OACs) and APT has not been fully elucidated. Among 3718 consecutive patients who underwent PCI, 302 patients were treated with both OACs and APT. We evaluated the association between PDB and 3-year all-cause mortality, as estimated by a time-updated Cox proportional hazard regression model. We performed nearest-neighbor matching on the propensity score to adjust the differences in baseline characteristics. Among 302 patients treated with OACs and APT, PDB was observed in 98 patients at a median time of 239 days. Patients experienced PDB had significantly higher incidence of 3-year all-cause mortality in the overall cohort and 94 propensity-score–matched pairs (hazard ratio 6.21, 95% confidence interval 3.29–11.72, P < 0.0001; and hazard ratio 6.13, 95% confidence interval 2.68–14.02, P < 0.0001, respectively). The risk of subsequent mortality was the highest within 180 days after PDB (58.3% within 180 days and 75.0% within 1 year). In conclusion, PDB was significantly associated with long-term mortality in patients taking both OACs and APT after PCI.

The Novel Inodilator ORM-3819 Relaxes Isolated Porcine Coronary Arteries: Role of Voltage-Gated Potassium Channel Activation Abstract: Relaxation and changes in the transmembrane potential of vascular smooth muscle induced by ORM-3819, a novel inodilating compound, were investigated in isolated porcine coronary arteries. Isometric tone was studied on arterial rings precontracted by KCl (30 mM), and resting membrane potential was investigated by a conventional microelectrode technique. ORM-3819 in the concentration range 0.38–230.6 µM evoked concentration-dependent relaxation with a maximum value of 58.1% and an effective concentration of the relaxing substance that caused 50% of maximum relaxation of 72.2 µM. The maximum hyperpolarization produced by ORM-3819 at a concentration of 120 µM (−2.6 ± 0.81 mV, N = 10) did not differ significantly from that induced by C-type natriuretic peptide (CNP), an endogenous hyperpolarizing mediator, at a concentration of 1.4 µM (−3.6 ± 0.38 mV, N = 17). The same effect elicited by the known inodilator levosimendan was less pronounced at a concentration of 3.7 µM: −1.82 ± 0.44 mV, N = 22 (P < 0.05 vs. CNP). The voltage-gated potassium channel inhibitor 4-aminopyridine, at a concentration of 5 mM, attenuated the relaxation induced by ORM-3819 at concentrations of 41.6 or 117.2 µM. These results suggest that ORM-3819 is a potent vasodilating agent able to relieve coronary artery vasospasm by causing hyperpolarization of vascular smooth muscle cells through processes involving activation of voltage-gated potassium channels.

Drugs to Inhibit the NLRP3 Inflammasome: Not Always On Target No abstract available

Carthamin Yellow Protects the Heart Against Ischemia/Reperfusion Injury With Reduced Reactive Oxygen Species Release and Inflammatory Response Abstract: Carthamin yellow (CY) is a flavonoid compound isolated from safflower, which is widely used clinically in China. It has various pharmacological effects including promoting blood circulation to remove blood stasis and alleviating pain. Ischemic heart disease is one of the main culprits of illness and death. Here, in this study, ex vivo and in vivo models were used to investigate whether CY reduces ischemia/reperfusion injury. In vitro experiments further verify and explain the potential mechanisms of CY cardioprotective function. Isolated hearts from male rats with or without CY pretreatment before ischemia which underwent 30-minute ischemia followed by 60-minute reperfusion showed that CY pretreatment significantly reduced the infarct size and lactate dehydrogenase release. The in vivo experiments also indicated CY preadministration (i.v.) reduced infarct size and improved the heart function, which was impaired by myocardial ischemia/reperfusion injury. The in vitro model on myocardial cell also showed that CY reduced ischemia/reperfusion injury by reducing the lactate dehydrogenase and reactive oxygen species (ROS) releasing. Eliminating ROS with N-acetylcysteine or preinject CY into rat jugular vein reduces the expression of IL-6, TNF-a, and, especially, IL-1b in an in vivo I/R model. Also, CY pretreatment strongly reduces ischemia/reperfusion-induced NLRP3 up-expression and caspase-1 activation. Our results indicated CY reduced ischemia–reperfusion injury when administered before reperfusion. The reduction in injury is accompanied by a reduced ROS release and decreased inflammatory response.

Role of Cytochrome p450 and Soluble Epoxide Hydrolase Enzymes and Their Associated Metabolites in the Pathogenesis of Diabetic Cardiomyopathy Abstract: A plethora of studies have demonstrated that cardiomyopathy represents a serious source of morbidity and mortality in patients with diabetes. Yet, the underlying mechanisms of diabetic cardiomyopathy are still poorly understood. Of interest, cytochrome P450 2J (CYP2J) and soluble epoxide hydrolase (sEH) are known to control the maintenance of cardiovascular health through the regulation of cardioprotective epoxyeicosatrienoic acids (EETs) and its less active products, dihydroxyeicosatrienoic acids (DHETs). Therefore, we examined the role of the aforementioned pathway in the development of diabetic cardiomyopathy. Our diabetic model initiated cardiomyopathy as indexed by the increase in the expression of hypertrophic markers such as NPPA. Furthermore, diabetic cardiomyopathy was associated with a low level of cardiac EETs and an increase of the DHETs/EETs ratio both in vivo and in cardiac cells. The modulation in EETs and DHETs was attributed to the increase of sEH and the decrease of CYP2J. Interestingly, the reduction of sEH attenuates cardiotoxicity mediated by high glucose in cardiac cells. Mechanistically, the beneficial effect of sEH reduction might be due to the decrease of phosphorylated ERK1/2 and p38. Overall, the present work provides evidence that diabetes initiates cardiomyopathy through the increase in sEH, the reduction of CYP2J, and the decrease of cardioprotective EETs.