Action and therapeutic targets of myosin light chain kinase, an important cardiovascular signaling mechanism.

The global incidence of cardiac diseases is increasing, imposing a substantial socioeconomic burden on healthcare systems. The pathogenesis of cardiovascular disease is complex and not fully understood, and the physiological function of the heart is inextricably linked to well-regulated cardiac muscle movement. Myosin light chain kinase (MLCK) is essential for myocardial contraction and diastole, cardiac electrophysiological homeostasis, vasoconstriction of vascular nerves and blood pressure regulation. In this sense, MLCK appears to be an attractive therapeutic target for cardiac diseases. MLCK participates in myocardial cell movement and migration through diverse pathways, including regulation of calcium homeostasis, activation of myosin light chain phosphorylation, and stimulation of vascular smooth muscle cell contraction or relaxation. Recently, phosphorylation of myosin light chains has been shown to be closely associated with the activation of myocardial exercise signaling, and MLCK mediates systolic and diastolic functions of the heart through the interaction of myosin thick filaments and actin thin filaments. It works by upholding the integrity of the cytoskeleton, modifying the conformation of the myosin head, and modulating innervation. MLCK governs vasoconstriction and diastolic function and is associated with the activation of adrenergic and sympathetic nervous systems, extracellular transport, endothelial permeability, and the regulation of nitric oxide and angiotensin II. Additionally, MLCK plays a crucial role in the process of cardiac aging. Multiple natural products/phytochemicals and chemical compounds, such as quercetin, cyclosporin, and ML-7 hydrochloride, have been shown to regulate cardiomyocyte MLCK. The MLCK-modifying capacity of these compounds should be considered in designing novel therapeutic agents. This review summarizes the mechanism of action of MLCK in the cardiovascular system and the therapeutic potential of reported chemical compounds in cardiac diseases by modifying MLCK processes.

Mendelian randomization of chronic hepatitis B and cardiovascular disease.

Background: Evidence from observational studies suggests that chronic hepatitis B (CHB) is associated with cardiovascular disease (CVD). However, results have been inconsistent and causality remains to be established. We utilized two-sample Mendelian randomization (MR) to investigate potential causal associations between CHB and CVD, including atherosclerosis, coronary heart disease, hypertension, and ischemic stroke. Methods: The analysis was conducted through genome-wide association studies (GWAS), considering chronic hepatitis B as the exposure and cardiovascular disease as the endpoint. The primary method for evaluating causality in this analysis was the inverse-variance weighted (IVW) technique. Additionally, we employed the weighted median, MR-Egger regression, weighted mode, and simple mode methods for supplementary analyses. Finally, heterogeneity tests, sensitivity analyses, and multiple effects analyses were conducted. Results: In a random-effects IVW analysis, we found that genetic susceptibility to chronic hepatitis B was associated with an increased risk of atherosclerosis [OR = 1.048, 95% CI (1.022-1.075), P = 3.08E-04], as well as an increased risk of coronary heart disease [OR = 1.039, 95% CI (1.006-1.072), P = 0.020]. However, it was found to be inversely correlated with ischemic stroke risk [OR = 0.972, 95% CI (0.957-0.988), P = 4.13E-04]. There was no evidence that chronic hepatitis B was associated with hypertension [OR = 1.021, 95% CI (0.994-1.049), P = 0.121]. Conclusion: Our research indicates that chronic hepatitis B has a correlation with an elevated risk of developing atherosclerosis and coronary heart disease, while it is associated with a decreased risk of experiencing an ischemic stroke.

The effects of CYP2C19 genotype polymorphism and clopidogrel resistance on ischemic event occurrence in patients with peripheral arterial disease undergoing revascularization: A prospective cohort study.

INTRODUCTION: Peripheral arterial disease (PAD) affects approximately 236 million people worldwide. Therefore, this study aimed to investigate the relationship between CYP2C19 genotype polymorphisms and clopidogrel resistance (CR) following revascularization in patients with PAD. MATERIALS AND METHODS: In total, 345 patients who underwent PAD revascularization were monitored for five years and risk factors for ischemic events were identified. Platelet reactivity and CYP2C19 genotypes were measured, and patients were classified as normal, intermediate, or poor metabolizers based on their genotypes. The study endpoint was defined as an ischemic event, that encompassed major adverse cardiovascular or limb events, or all-cause death. RESULTS: In this study, ischemic events following PAD revascularization were associated with patient age, prior minor amputation, the Rutherford category before revascularization, indications for revascularization, index ankle-branchial index before revascularization, CYP2C19 phenotypes, and CR. Intermediate and poor metabolism, the Rutherford category before revascularization, and CR were independent risk factors for ischemic events in patients after PAD revascularization. Similarly, intermediate and poor metabolism, the Rutherford category before revascularization, and CR were independent risk factors for ischemic events in patients with PAD after revascularization within five years. Intermediate and poor metabolizers had a higher platelet reactivity and risk of CR than normal metabolizers. However, poor metabolizers had a higher platelet reactivity and risk of CR than intermediate metabolizers. Furthermore, the hazard ratio for ischemic events increased with platelet reactivity. This effect was more prevalent in intermediate and poor metabolizers than in normal metabolizers. CONCLUSIONS: Ischemic events in patients after PAD revascularization were affected by independent risk factors. Decreased clopidogrel metabolism increased the platelet reactivity and CR in patients after PAD revascularization. Furthermore, high platelet reactivity was associated with an increased risk of ischemic events in patients with intermediate and poor metabolism.