Journal of Molecular and Cellular Cardiology

Obesity and metabolic disorders are increasing in epidemic proportions, leading to poor outcomes including heart failure. With a growing recognition of the effect of adipose tissue dysfunction on heart disease, it is less well understood how the heart can influence systemic metabolic homeostasis. Even less well understood is sex differences in cardiometabolic responses. Previously, our lab investigated the role of the amino-terminus of GRK2 in cardiometabolic remodeling using transgenic mice with cardiac restricted expression of a short peptide, βARKnt...

At least seven cell death programs are activated during myocardial infarction (MI), but which are most important in causing heart damage is not understood. Two of these programs are mitochondrial-dependent necrosis and apoptosis. The canonical function of the pro-cell death BCL-2 family proteins BAX and BAK is to mediate permeabilization of the outer mitochondrial membrane during apoptosis allowing apoptogen release. BAX has also been shown to sensitize cells to mitochondrial-dependent necrosis, although the underlying mechanisms remain ill-defined...

BACKGROUND: The small conductance Ca2+ -activated K+ current (ISK ) is a potential therapeutic target for treating atrial fibrillation. AIM: To clarify, in rabbit and human atrial cardiomyocytes, the intracellular [Ca2+ ]-sensitivity of ISK , and its contribution to action potential (AP) repolarisation, under physiological conditions. METHODS: Whole-cell-patch clamp, fluorescence microscopy: to record ion currents, APs and [Ca2+ ]i ; 35-37°C...

No abstract text is available yet for this article.

BACKGROUND: Mitochondrial dysfunction of macrophage-mediated inflammatory response plays a key pathophysiological process in myocardial infarction (MI). Calpains are a well-known family of calcium-dependent cysteine proteases that regulate a variety of processes, including cell adhesion, proliferation, and migration, as well as mitochondrial function and inflammation. CAPNS1, the common regulatory subunit of calpain-1 and 2, is essential for the stabilization and activity of the catalytic subunit...

Peroxisome proliferator-activated receptor (PPAR) δ is a major transcriptional regulator of cardiac energy metabolism with pleiotropic properties, including anti-inflammatory, anti-oxidative and cardioprotective action. In this study, we sought to investigate whether pharmacological activation of PPARδ via intraperitoneal administration of the selective ligand GW0742 could ameliorate heart failure and mitochondrial dysfunction that have been previously reported in a characterized genetic model of heart failure, the desmin null mice (Des-/- )...

Cardiomyocyte proliferation is a difficult phenomenon to capture and prove. Here we employ a retrospective analysis of single cell ventricular suspensions to definitively identify cardiomyocytes that have completed cell division. Through this analysis we determined that the capacity of cardiomyocytes to re-enter the cell cycle and complete cell division after injury are separate and variable traits. Further, we provide evidence that Tnni3k definitively influences both early and final stages of the cell cycle...

Despite the dramatic improvements in the management of patients with chronic heart failure which have occurred over the last decades, some of them still exhaust conventional drug-based therapies without being eligible for more aggressive options like heart transplantation or implantation of a left ventricular assist device. Cell therapy has thus emerged as a possible means of filling this niche. Multiple cell types have now been tested both in the laboratory but also in the clinics and it is fair to acknowledge that none of the clinical trials have yet conclusively proven the efficacy of cell-based approaches...

BACKGROUND: Among the monogenic inherited causes of atrial fibrillation is the short QT syndrome (SQTS), a rare channelopathy causing atrial and ventricular arrhythmias. One of the limitations in studying the mechanisms and optimizing treatment of SQTS-related atrial arrhythmias has been the lack of relevant human atrial tissues models. OBJECTIVE: To generate a unique model to study SQTS-related atrial arrhythmias by combining the use of patient-specific human induced pluripotent stem cells (hiPSCs), atrial-specific differentiation schemes, two-dimensional tissue modeling, optical mapping, and drug testing...

Cardiovascular calcification can occur in vascular and valvular structures and is commonly associated with calcium deposition and tissue mineralization leading to stiffness and dysfunction. Patients with chronic kidney disease and associated hyperphosphatemia have an elevated risk for coronary artery calcification (CAC) and calcific aortic valve disease (CAVD). However, there is mounting evidence to suggest that the susceptibility and pathobiology of calcification in these two cardiovascular structures may be different, yet clinically they are similarly treated...

No abstract text is available yet for this article.

Although the myocardial renewal rate in the adult mammalian heart is quite low, recent studies have identified genetic variants which can impact the degree of cardiomyocyte cell cycle reentry. Here we use the compound interest law to model the level of regenerative growth over time in mice exhibiting different rates of cardiomyocyte cell cycle reentry following myocardial injury. The modeling suggests that the limited ability of S-phase adult cardiomyocytes to progress through cytokinesis, rather than the ability to reenter the cell cycle per se, is a major contributor to the low levels of intrinsic regenerative growth in the adult myocardium...

Cardiovascular disease is the leading cause of mortality and morbidity worldwide. Despite improvements in the standard of care for patients with heart diseases, including innovation in pharmacotherapy and surgical interventions, none have yet been proven effective to prevent the progression to heart failure. Cardiac transplantation is the last resort for patients with severe heart failure, but donor shortages remain a roadblock. Cardiac regenerative strategies include cell-based therapeutics, gene therapy, direct reprogramming of non-cardiac cells, acellular biologics, and tissue engineering methods to restore damaged hearts...

No abstract text is available yet for this article.

No abstract text is available yet for this article.

No abstract text is available yet for this article.

Cardiac function is a dynamic process that must adjust efficiently to the immediate demands of physical state and activity. So too, the metabolic support of cardiac function is a dynamic process that must respond, in time, to the demands of cardiac function and viability. Flux through metabolic pathways provides chemical energy and generates signaling molecules that regulate activity among intracellular compartments to meet these demands. Thus, flux through metabolic pathways provides a dynamic mode of support of cardiomyocytes during physiological and pathophysiological challenges...

Diabetes enhances myocardial ischemic/reperfusion (MI/R) injury via an incompletely understood mechanism. Adiponectin (APN) is a cardioprotective adipokine suppressed by diabetes. However, how hypoadiponectinemia exacerbates cardiac injury remains incompletely understood. Dysregulation of miRNAs plays a significant role in disease development. However, whether hypoadiponectinemia alters cardiac miRNA profile, contributing to diabetic heart injury, remains unclear. Methods and Results: Wild-type (WT) and APN knockout (APN-KO) mice were subjected to MI/R...

Cardiac excitation-contraction coupling (ECC) depends on Ca2+ release from intracellular stores via ryanodine receptors (RyRs) triggered by L-type Ca2+ channels (LCCs). Uncertain numbers of RyRs and LCCs form 'couplons' whose activation produces Ca2+ sparks, which summate to form a cell-wide Ca2+ transient that switches on contraction. Voltage (Vm ) changes during the action potential (AP) and stochasticity in channel gating should create variability in Ca2+ spark timing, but Ca2+ transient wavefronts have remarkable uniformity...

The reprogramming of somatic cells to a spontaneously contracting cardiomyocyte-like state using defined transcription factors has proven successful in mouse fibroblasts. However, this process has been less successful in human cells, thus limiting the potential clinical applicability of this technology in regenerative medicine. We hypothesized that this issue is due to a lack of cross-species concordance between the required transcription factor combinations for mouse and human cells. To address this issue, we identified novel transcription factor candidates to induce cell conversion between human fibroblasts and cardiomyocytes, using the network-based algorithm Mogrify...