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Mitochondrial-associated membranes (MAMs) are known to modulate organellar and cellular functions and can subsequently affect pathophysiology including myocardial ischemia-reperfusion (IR) injury. Thus, identifying molecular targets in MAMs that regulate the outcome of IR injury will hold a key to efficient therapeutics. Here, we found chloride intracellular channel protein (CLIC4) presence in MAMs of cardiomyocytes and demonstrate its role in modulating ER and mitochondrial calcium homeostasis under physiological and pathological conditions. In a murine model, loss of CLIC4 increased myocardial infarction and substantially reduced cardiac function after IR injury. CLIC4 null cardiomyocytes showed increased apoptosis and mitochondrial dysfunction upon hypoxia-reoxygenation injury in comparison to wild-type cardiomyocytes. Overall, our results indicate that MAM-CLIC4 is a key mediator of cellular response to IR injury and therefore may have a potential implication on other pathophysiological processes.

Introduction: MicroRNA-1 (miR1) is an evolutionarily conserved, striated muscle-enriched microRNA and plays critical roles in regulation of the development and physiology of the heart. It has been found that miR1 was downregulated in various types of cardiac diseases. We observed that, compared to that in young mice (age 3-4 months), the expression of miR1 was significantly decreased to the level of 12.5±4.0% in the heart of aged animals (age 18 months). Hypothesis: We hypothesized that miR1 deficiency is a major etiology in diseased and/or aged hearts. In the mammalian genome, two distinct genes, miR1-1 and miR1-2 that are located on two chromosomes, generate identical mature miR1. Methods and Results: To study the hypothesis, we generated miR1-75% knockdown (75%KD) mice by crossbreeding miR1-1 knockout (KO) and miR1-2 KO animals and found that miR1-75%KD mice could survive to adult age with a relatively higher mortality, while miR1-100%-KO is postnatal lethal. The ejection fraction and fraction shortening of 75%KD hearts was significantly decreased than that of WT animals. Electrocardiogram showed that, compared to the WT group, 75%KD hearts had significantly slower heart rates with shorter PR interval and prolonged QRS interval with observed premature ventricular contractions. Optical mapping of ex vivo hearts revealed significantly slower ventricular conduction velocity in 75%KD hearts. Compared to WT cells, 75%KD ventricular cardiomyocytes had hyperpolarized RMPs with prolonged action potentials, and showed significantly decreased sarcomere shortening. Proteomic assays found that proteins of mitochondrial ATP synthesis and electron transport were significantly downregulated in 75%KD hearts. Conclusions: We conclude that the deficiency of miR1 is a major etiological factor of cardiac electrical and metabolic remodeling in the heart. Restoring the normal level of miR1 in the heart could be a critical and effective therapeutic strategy to prevent and/or treat heart diseases.

Cigarette smoking is the most preventable risk factor related to cardiovascular morbidity and mortality. Tobacco usage has declined in recent years; however, the use of alternative nicotine delivery methods, particularly e-cigarettes, has increased exponentially despite limited data on their short- and long-term safety and efficacy. Due to their unique properties, the impact of e-cigarettes on cardiovascular physiology is not fully known. Here, we summarize both preclinical and clinical data extracted from short- and long-term studies on the cardiovascular effects of e-cigarette use. Current findings support that e-cigarettes are not a harm-free alternative to tobacco smoke. However, the data are primarily derived from acute studies. The impact of chronic e-cigarette exposure is essentially unstudied. To explore the uniqueness of e-cigarettes, we contemplate the cardiovascular effects of individual e-cigarette constituents. Overall, data suggest that exposure to e-cigarettes could be a potential cardiovascular health concern. Further preclinical research and randomized trials are needed to expand basic and clinical investigations before considering e-cigarettes safe alternatives to conventional cigarettes.

Cardiovascular disease (CVD) remains the most common cause of adult morbidity and mortality in developed nations. As a result, predisposition for CVD is increasingly important to understand. Ankyrins are intracellular proteins required for the maintenance of membrane domains. Canonical ankyrin-G (AnkG) has been shown to be vital for normal cardiac function, specifically cardiac excitability, via targeting and regulation of the cardiac voltage-gated sodium channel. Noncanonical (giant) AnkG isoforms play a key role in neuronal membrane biogenesis and excitability, with evidence for human neurologic disease when aberrant. However, the role of giant AnkG in cardiovascular tissue has yet to be explored. Here, we identify giant AnkG in the myocardium and identify that it is enriched in 1-week-old mice. Using a new mouse model lacking giant AnkG expression in myocytes, we identify that young mice displayed a dilated cardiomyopathy phenotype with aberrant electrical conduction and enhanced arrhythmogenicity. Structural and electrical dysfunction occurred at 1 week of age, when giant AnkG was highly expressed and did not appreciably change in adulthood until advanced age. At a cellular level, loss of giant AnkG results in delayed and early afterdepolarizations. However, surprisingly, giant AnkG cKO myocytes display normal INa, but abnormal myocyte contractility, suggesting unique roles of the large isoform in the heart. Finally, transcript analysis provided evidence for unique pathways that may contribute to the structural and electrical findings shown in giant AnkG cKO animals. In summary, we identify a critical role for giant AnkG that adds to the diversity of ankyrin function in the heart.