Journal of molecular and cellular cardiology最新文献

Atrial fibrillation (AF), with its significant associated morbidity and mortality contributes to significant healthcare utilisation and expenditure. Given its progressively rising incidence, strategies to limit AF development and progression are urgently needed. Lifestyle modification is a potentially potent but underutilised weapon against the AF epidemic. The purpose of this article is to review the role of lifestyle factors as risk factors for AF, outline potential mechanisms of pathogenesis and examine the available evidence for lifestyle intervention in primary and secondary AF prevention. It will also highlight the need for investment by physicians, researchers, health services and governments in order to facilitate delivery of the comprehensive, multidisciplinary AF care that is required to manage this complex and multifactorial disease.

Background

Hypoxia-induced pulmonary artery hypertension (HPH) is a complication of chronic hypoxic lung disease and the third most common type of pulmonary artery hypertension (PAH). Epigenetic mechanisms play essential roles in the pathogenesis of HPH. N6-methyladenosine (m6A) is an important modified RNA nucleotide involved in a variety of biological processes and an important regulator of epigenetic processes. To date, the precise role of m6A and regulatory molecules in HPH remains unclear.

Methods

HPH model and pulmonary artery smooth muscle cells (PASMCs) were constructed from which m6A changes were observed and screened for AlkB homolog 5 (Alkbh5). Alkbh5 knock-in (KI) and knock-out (KO) mice were constructed to observe the effects on m6A and evaluate right ventricular systolic pressure (RVSP), left ventricular and septal weight [RV/(LV + S)], and pulmonary vascular remodeling in the context of HPH. Additionally, the effects of Alkbh5 knockdown using adenovirus were examined in vitro on m6A, specifically in PASMCs with regard to proliferation, migration and cytochrome P450 1A1 (Cyp1a1) mRNA stability.

Results

In both HPH mice lung tissues and hypoxic PASMCs, a decrease in m6A was observed, accompanied by a significant up-regulation of Alkbh5 expression. Loss of Alkbh5 attenuated the proliferation and migration of hypoxic PASMCs in vitro, with an associated increase in m6A modification. Furthermore, Alkbh5 KO mice exhibited reduced RVSP, RV/(LV + S), and attenuated vascular remodeling in HPH mice. Mechanistically, loss of Alkbh5 inhibited Cyp1a1 mRNA decay and increased its expression through an m6A-dependent post-transcriptional mechanism, which hindered the proliferation and migration of hypoxic PASMCs.

Conclusion

The current study highlights the loss of Alkbh5 impedes the proliferation and migration of PASMCs by inhibiting post-transcriptional Cyp1a1 mRNA decay in an m6A-dependent manner.

Atrial fibrillation (AF) is the most common cardiac rhythm disorder, often occurring in the setting of atrial distension and elevated myocardialstretch. While various mechano-electrochemical signal transduction pathways have been linked to AF development and progression, the underlying molecular mechanisms remain poorly understood, hampering AF therapies. In this review, we describe different aspects of stretch-induced electro-anatomical remodeling as seen in animal models and in patients with AF. Specifically, we focus on cellular and molecular mechanisms that are responsible for mechano-electrochemical signal transduction and the development of ectopic beats triggering AF from pulmonary veins, the most common source of paroxysmal AF. Furthermore, we describe structural changes caused by stretch occurring before and shortly after the onset of AF as well as during AF progression, contributing to longstanding forms of AF. We also propose mechanical stretch as a new dimension to the concept “AF begets AF”, in addition to underlying diseases. Finally, we discuss the mechanisms of these electro-anatomical alterations in a search for potential therapeutic strategies and the development of novel antiarrhythmic drugs targeted at the components of mechano-electrochemical signal transduction not only in cardiac myocytes, but also in cardiac non-myocyte cells.

Background

Hypothermic ischemia-reperfusion arrhythmia is a common complication of cardiothoracic surgery under cardiopulmonary bypass, but few studies have focused on this type of arrhythmia. Our prior study discovered reduced myocardial Cx43 protein levels may be linked to hypothermic reperfusion arrhythmias. However, more detailed molecular mechanism research is required.

Method

The microRNA and mRNA expression levels in myocardial tissues were detected by real-time quantitative PCR (RT-qPCR). Besides, the occurrence of hypothermic reperfusion arrhythmias and changes in myocardial electrical conduction were assessed by electrocardiography and ventricular epicardial activation mapping. Furthermore, bioinformatics analysis, applying antagonists of miRNA, western blotting, immunohistochemistry, a dual luciferase assay, and pearson correlation analysis were performed to investigate the underlying molecular mechanisms.

Results

The expression level of novel-miR-17 was up-regulated in hypothermic ischemia-reperfusion myocardial tissues. Inhibition of novel-miR-17 upregulation ameliorated cardiomyocyte edema, reduced apoptosis, increased myocardial electrical conduction velocity, and shortened the duration of reperfusion arrhythmias. Mechanistic studies showed that novel-miR-17 reduced the expression of Cx43 by directly targeting Gja1 while mediating the activation of the PKC/c-Jun signaling pathway.

Conclusion

Up-regulated novel-miR-17 is a newly discovered pro-arrhythmic microRNA that may serve as a potential therapeutic target and biomarker for hypothermic reperfusion arrhythmias.

The YTH-domain family (YTHDF) of RNA binding proteins can control gene expression at the post-transcriptional level by regulating mRNAs with N⁶-methyladenosine (m⁶A) modifications. Despite the established importance of m⁶A in the heart, the cardiac role of specific m⁶A-binding proteins remains unclear. Here, we characterized the function of YTHDF1 in cardiomyocytes using a newly generated cardiac-restricted mouse model. Deletion of YTHDF1 in adult cardiomyocytes led to hypertrophy, fibrosis, and dysfunction. Using mass spectrometry, we identified the necessity of YTHDF1 for the expression of cardiomyocyte membrane raft proteins. Specifically, YTHDF1 bound to m⁶A-modified Caveolin 1 (Cav1) mRNA and favored its translation. We further demonstrated that YTHDF1 regulates downstream ERK signaling. Altogether, our findings highlight a novel role for YTHDF1 as a post-transcriptional regulator of caveolar proteins which is necessary for the maintenance of cardiac function.

Ferroptosis is an iron-dependent programmed cell death form resulting from lipid peroxidation damage, it plays a key role in organ damage and tumor development from various causes. Sepsis leads to severe host response after infection with high mortality. The long non-coding RNAs (LncRNAs) are involved in different pathophysiological mechanisms of multiple diseases. Here, we used cecal ligation and puncture (CLP) operation to mimic sepsis induced myocardial injury (SIMI) in mouse model, and LncRNAs and mRNAs were profiled by Arraystar mouse LncRNA Array V3.0. Based on the microarray results, 552 LncRNAs and 520 mRNAs were differentially expressed in the sham and CLP groups, among them, LncRNA Lcn2–204 was the highest differentially expressed up-regulated LncRNA. Iron metabolism disorder was involved in SIMI by bioinformatics analysis, meanwhile, myocardial iron content and lipocalin-2 (Lcn2) protein expressions were increased. The CNC network comprised 137 positive interactions and 138 negative interactions. Bioinformatics analysis showed several iron-related terms were enriched and six genes (Scara5, Tfrc, Lcn2, Cp, Clic5, Ank1) were closely associated with iron metabolism. Then, we constructed knockdown LncRNA Lcn2–204 targeting myocardium and found that it ameliorated cardiac injury in mouse sepsis model through modulating iron overload and ferroptosis. In addition, we found that LncRNA Lcn2–204 was involved in the regulation of Lcn2 expression in septic myocardial injury. Based on these findings, we conclude that iron overload and ferroptosis are the key mechanisms leading to myocardial injury in sepsis, knockdown of LncRNA Lcn2–204 plays the cardioprotective effect through inhibition of iron overload, ferroptosis and Lcn2 expression. It may provide a novel therapeutic approach to ameliorate sepsis-induced myocardial injury.

Endothelial dysfunction is a central contributor to the development of most cardiovascular diseases and is characterised by the reduced synthesis or bioavailability of the vasodilator nitric oxide together with other abnormalities such as inflammation, senescence, and oxidative stress. The use of patient-specific and genome-edited human pluripotent stem cell-derived endothelial cells (hPSC-ECs) has shed novel insights into the role of endothelial dysfunction in cardiovascular diseases with strong genetic components such as genetic cardiomyopathies and pulmonary arterial hypertension. However, their utility in studying complex multifactorial diseases such as atherosclerosis, metabolic syndrome and heart failure poses notable challenges. In this review, we provide an overview of the different methods used to generate and characterise hPSC-ECs before comprehensively assessing their effectiveness in cardiovascular disease modelling and high-throughput drug screening. Furthermore, we explore current obstacles that will need to be overcome to unleash the full potential of hPSC-ECs in facilitating patient-specific precision medicine. Addressing these challenges holds great promise in advancing our understanding of intricate cardiovascular diseases and in tailoring personalised therapeutic strategies.

While exercise-mediated vasoregulation in the myocardium is understood to be governed by autonomic, myogenic, and metabolic-mediated mechanisms, we do not yet understand the spatial heterogeneity of vasodilation or its effects on microvascular flow patterns and oxygen delivery. This study uses a simulation and modeling approach to explore the mechanisms underlying the recruitment of myocardial perfusion and oxygen delivery in exercise. The simulation approach integrates model components representing: whole-body cardiovascular hemodynamics, cardiac mechanics and myocardial work; myocardial perfusion; and myocardial oxygen transport. Integrating these systems together, model simulations reveal: (1.) To match expected flow and transmural flow ratios at increasing levels of exercise, a greater degree of vasodilation must occur in the subendocardium compared to the subepicardium. (2.) Oxygen extraction and venous oxygenation are predicted to substantially decrease with increasing exercise level preferentially in the subendocardium, suggesting that an oxygen-dependent error signal driving metabolic mediated recruitment of flow would be operative only in the subendocardium. (3.) Under baseline physiological conditions approximately 4% of the oxygen delivered to the subendocardium may be supplied via retrograde flow from coronary veins.

Coronary microvascular disease (CMD) and impaired coronary blood flow control are defects that occur early in the pathogenesis of heart failure in cardiometabolic conditions, prior to the onset of atherosclerosis. In fact, recent studies have shown that CMD is an independent predictor of cardiac morbidity and mortality in patients with obesity and metabolic disease. CMD is comprised of functional, structural, and mechanical impairments that synergize and ultimately reduce coronary blood flow in metabolic disease and in other co-morbid conditions, including transplant, autoimmune disorders, chemotherapy-induced cardiotoxicity, and remote injury-induced CMD. This review summarizes the contemporary state-of-the-field related to CMD in metabolic and these other co-morbid conditions based on mechanistic data derived mostly from preclinical small- and large-animal models in light of available clinical evidence and given the limitations of studying these mechanisms in humans. In addition, we also discuss gaps in current understanding, emerging areas of interest, and opportunities for future investigations in this field.