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Objectives: Angiotensin II (Ang II) plays a key role in the regulation of myocardial hypertrophy via downstream cysteine-rich transmembrane bone morphogenetic protein regulator 1 (Crim1). However, it is still unclear whether Crim1 is involved in ionic channel remodeling. The study aimed to explore the effects of Crim1 on transient outward potassium current (Ito) and Kv4.2 (the main subunit of Ito channel) expression in hypertrophic ventricular cardiomyocytes. Materials and Methods: The ventricular cardiomyocytes were isolated from the neonatal rats. Hypertrophy was induced by Ang II. Crim1 expression was modulated by using adenovirus transfection. The expression of myosin heavy chain beta (ß-MHC), Crim1, and Kv4.2 was determined by RT-qPCR and western blot. The cellular surface area was assessed using Image J software. Ito was recorded by the whole-cell patch clamp technique. Results: Ang II-induced hypertrophy in cardiomyocytes was identified by their larger cellular surface area and higher mRNA expression of ß-MHC. Ang II significantly decreased the expression of Crim1 and Kv4.2 and reduced Ito current density. However, Crim1 overexpression abolished the Ang II-induced hypertrophy and preserved the expression of Kv4.2 and Ito current density. Conclusion: Crim1 overexpression inhibits Ang II-induced hypertrophy and preserves Ito current density via up-regulating Kv4.2 in ventricular cardiomyocytes from neonatal rats. Crim1 could have a role in the development of ventricular arrhythmia in hypertrophic hearts.

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It has been shown that the activation of calcineurin is involved in regulating ion channel remodeling in hypertrophic cardiomyocytes. But the precise role of calcineurin in the regulation of transient outward potassium current (I to), an ion channel associated with fatal arrhythmia, remains controversial. This study aimed to examine the effects of calcineurin Aß (CnAß) gene knockdown on I to channel remodeling and action potential duration (APD) in the hypertrophic ventricular myocytes of neonatal rats. Results showed that phenylephrine stimulation caused hypertrophy of ventricular myocytes, upregulation of CnAß protein expression, downregulation of Kv4.2 mRNA and protein expression, a decrease in I to current density, and prolongation of APD. CnAß gene knockdown significantly inhibited the effects of phenylephrine stimulation. Our data indicate that CnAß gene knockdown can inhibit I to channel remodeling and APD prolongation in hypertrophic neonatal rat ventricular myocytes. This finding suggests that calcineurin may be a potential target for the prevention of malignant ventricular arrhythmia in a hypertrophic heart.

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Chronic kidney disease (CKD) significantly increases cardiovascular risk. In advanced CKD stages, accumulation of toxic circulating metabolites and mineral metabolism alterations triggers vascular calcification, characterized by vascular smooth muscle cell (VSMC) transdifferentiation and loss of the contractile phenotype. Phenotypic modulation of VSMC occurs with significant changes in gene expression. Even though ion channels are an integral component of VSMC function, the effects of uremia on ion channel remodeling has not been explored. We used an in vitro model of uremia-induced calcification of human aorta smooth muscle cells (HASMCs) to study the expression of 92 ion channel subunit genes. Uremic serum-induced extensive remodeling of ion channel expression consistent with loss of excitability but different from the one previously associated with transition from contractile to proliferative phenotypes. Among the ion channels tested, we found increased abundance and activity of voltage-dependent K+ channel Kv1.3. Enhanced Kv1.3 expression was also detected in aorta from a mouse model of CKD. Pharmacological inhibition or genetic ablation of Kv1.3 decreased the amount of calcium phosphate deposition induced by uremia, supporting an important role for this channel on uremia-induced VSMC calcification.

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The function of the sinoatrial node (SAN), the pacemaker of the heart, declines with age, resulting in increased incidence of sinoatrial node dysfunction (SND) in older adults. The present study assesses potential ionic mechanisms underlying age associated SND. Two group studies have identified complex and various changes in some of membrane ion channels in aged rat SAN, the first group (Aging Study-1) indicates a considerable changes of gene expression with up-regulation of mRNA in ion channels of Cav1.2, Cav1.3 and KvLQT1, Kv4.2, and the Ca2+ handling proteins of SERCA2a, and down-regulation of Cav3.1, NCX, and HCN1 and the Ca2+-clock proteins of RYR2. The second group (Aging Study-2) suggests a different pattern of changes, including down regulation of Cav1.2, Cav1.3 and HCN4, and RYR2, and an increase of NCX and SERCA densities and proteins. Although both data sets shared a similar finding for some specific ion channels, such as down regulation of HCN4, NCX, and RYR2, there are contradictory changes for some other membrane ion channels, such as either up-regulation or down-regulation of Cav1.2, NCX and SERCA2a in aged rat SAN. The present study aims to test a hypothesis that age-related SND may arise from different ionic and molecular remodeling patterns. To test this hypothesis, a mathematical model of the electrical action potential of rat SAN myocytes was modified to simulate the functional impact of age-induced changes on membrane ion channels and intracellular Ca2+ handling as observed in Aging Study-1 and Aging Study-2. The role and relative importance of each individually remodeled ion channels and Ca2+-handling in the two datasets were evaluated. It was shown that the age-induced changes in ion channels and Ca2+-handling, based on either Aging Study-1 or Aging Study-2, produced similar bradycardic effects as manifested by a marked reduction in the heart rate (HR) that matched experimental observations. Further analysis showed that although the SND arose from an integrated action of all remodeling of ion channels and Ca2+-handling in both studies, it was the change to I CaL that played the most important influence.

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Circadian rhythms are involved in many physiological and pathological processes in different tissues, including the heart. Circadian rhythms play a critical role in adverse cardiac function with implications for heart failure and sudden cardiac death, highlighting a significant contribution of circadian mechanisms to normal sinus rhythm in health and disease. Cardiac arrhythmias are a leading cause of morbidity and mortality in patients with heart failure and likely cause ∼250,000 deaths annually in the United States alone; however, the molecular mechanisms are poorly understood. This suggests the need to improve our current understanding of the underlying molecular mechanisms that increase vulnerability to arrhythmias. Obesity and its associated pathologies, including diabetes, have emerged as dangerous disease conditions that predispose to adverse cardiac electrical remodeling leading to fatal arrhythmias. The increasing epidemic of obesity and diabetes suggests vulnerability to arrhythmias will remain high in patients. An important objective would be to identify novel and unappreciated cellular mechanisms or signaling pathways that modulate obesity and/or diabetes. In this review we discuss circadian rhythms control of metabolic and environmental cues, cardiac ion channels, and mechanisms that predispose to supraventricular and ventricular arrhythmias including hormonal signaling and the autonomic nervous system, and how understanding their functional interplay may help to inform the development and optimization of effective clinical and therapeutic interventions with implications for chronotherapy.

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Cardiac arrhythmias are a leading cause of cardiovascular death. It has long been accepted that life-threatening cardiac arrhythmias (ventricular tachycardia, ventricular fibrillation, and sudden cardiac death) are more likely to occur in the morning after waking. It is perhaps less well recognized that there is a circadian rhythm in cardiac pacemaking and other electrophysiological properties of the heart. In addition, there is a circadian rhythm in other arrhythmias, for example, bradyarrhythmias and supraventricular arrhythmias. Two mechanisms may underlie this finding: (1) a central circadian clock in the suprachiasmatic nucleus in the hypothalamus may directly affect the electrophysiology of the heart and arrhythmogenesis via various neurohumoral factors, particularly the autonomic nervous system; or (2) a local circadian clock in the heart itself (albeit under the control of the central clock) may drive a circadian rhythm in the expression of ion channels in the heart, which in turn varies arrhythmic substrate. This review summarizes the current understanding of the circadian rhythm in cardiac electrophysiology, arrhythmogenesis, and the underlying molecular mechanisms.

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RATIONALE: Downregulation of the pacemaking ion channel, HCN4 (hyperpolarization-activated cyclic nucleotide gated channel 4), and the corresponding ionic current, If, underlies exercise training-induced sinus bradycardia in rodents. If this occurs in humans, it could explain the increased incidence of bradyarrhythmias in veteran athletes, and it will be important to understand the underlying processes. OBJECTIVE: To test the role of HCN4 in the training-induced bradycardia in human athletes and investigate the role of microRNAs (miRs) in the repression of HCN4. METHODS AND RESULTS: As in rodents, the intrinsic heart rate was significantly lower in human athletes than in nonathletes, and in all subjects, the rate-lowering effect of the HCN selective blocker, ivabradine, was significantly correlated with the intrinsic heart rate, consistent with HCN repression in athletes. Next-generation sequencing and quantitative real-time reverse transcription polymerase chain reaction showed remodeling of miRs in the sinus node of swim-trained mice. Computational predictions highlighted a prominent role for miR-423-5p. Interaction between miR-423-5p and HCN4 was confirmed by a dose-dependent reduction in HCN4 3'-untranslated region luciferase reporter activity on cotransfection with precursor miR-423-5p (abolished by mutation of predicted recognition elements). Knockdown of miR-423-5p with anti-miR-423-5p reversed training-induced bradycardia via rescue of HCN4 and If. Further experiments showed that in the sinus node of swim-trained mice, upregulation of miR-423-5p (intronic miR) and its host gene, NSRP1, is driven by an upregulation of the transcription factor Nkx2.5. CONCLUSIONS: HCN remodeling likely occurs in human athletes, as well as in rodent models. miR-423-5p contributes to training-induced bradycardia by targeting HCN4. This work presents the first evidence of miR control of HCN4 and heart rate. miR-423-5p could be a therapeutic target for pathological sinus node dysfunction in veteran athletes.

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Obesity and its associated metabolic dysregulation leading to metabolic syndrome is an epidemic that poses a significant public health problem. More than one-third of the world population is overweight or obese leading to enhanced risk of cardiovascular disease (CVD) incidence and mortality. Obesity predisposes to atrial fibrillation, ventricular, and supraventricular arrhythmias; conditions that are underlain by dysfunction in electrical activity of the heart. To date, current therapeutic options for cardiomyopathy of obesity are limited, suggesting that there is considerable room for development of therapeutic interventions with novel mechanisms of action that will help normalize rhythm in obese patients. Emerging candidates for modulation by obesity are cardiac ion channels and Ca handling proteins. However, the underlying molecular mechanisms of the impact of obesity on these channels/Ca handling proteins remain incompletely understood. Obesity is marked by accumulation of adipose tissue associated with a variety of adverse adaptations including dyslipidemia (or abnormal levels of serum free fatty acids), increased secretion of pro-inflammatory cytokines, fibrosis, hyperglycemia, and insulin resistance, that will cause electrical remodeling and thus predispose to arrhythmias. Further, adipose tissue is also associated with the accumulation of subcutaneous and visceral fat, which are marked by distinct signaling mechanisms. Thus, there may also be functional differences in the outcome of regional distribution of fat deposits on ion channel/Ca handling proteins expression. Evaluating alterations in their functional expression in obesity will lead to progress in the knowledge about the mechanisms responsible for obesity-related arrhythmias. These advances are likely to reveal new targets for pharmacological modulation. The objective of this article is to review cardiac ion channel/Ca handling proteins remodeling that predispose to arrhythmias. Understanding how obesity and related mechanisms lead to cardiac electrical remodeling is likely to have a significant medical and economic impact.

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In the present study, we examined if and how cardiac ion channels are modified by type 2 diabetes mellitus (T2DM). Subendocardial (Endo) myocytes and subepicardial (Epi) myocytes were isolated from left ventricles of Otsuka-Long-Evans-Tokushima Fatty rats (OLETF) rats, a rat model of T2DM, and Otsuka-Long-Evans-Tokushima (LETO) rats (nondiabetic control rats). Endo and Epi myocytes were used for whole cell patch-clamp recordings and for protein and mRNA analyses. Action potential durations in Endo and Epi myocytes were longer in OLETF rats than in LETO rats, and the difference was larger in Endo myocytes. Steady-state transient outward K+ current (Ito) density was reduced in Endo but not Epi myocytes of OLETF rats compared with LETO rats, although the contribution of the fast component of Ito recovery from inactivation was smaller in both Endo and Epi myocytes of OLETF rats than in LETO rats. Kv4.2 protein was reduced only in Endo myocytes in OLETF rats, although voltage-gated K+ channel-interacting protein 2 (KChIP2) protein levels in both Endo and Epi myocytes were lower in OLETF rats than in LETO rats. Corresponding regional differences in mRNA levels of KChIP2 and Kv4.2 were observed between OLETF and LETO rats. mRNA levels of Iroquois homeobox 5 in Endo myocytes were 53% higher in OLETF rats than in LETO rats. Densities of inward rectifier K+ current and L-type Ca2+ current and mRNA levels of Kv4.3 and Kv1.4 were similar in OLETF and LETO rats. In conclusion, T2DM induces Endo-predominant prolongation of the action potential duration via a reduction of the fast component of Ito recovery from inactivation and reduced steady-state Ito, in which downregulation of Kv4.2 and KChIP2 may be involved. Increased Iroquois homeobox 5 expression may underlie Kv4.2 downregulation in T2DM.

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