Cardiovascular Effects and Benefits of Exercise

It is widely accepted that regular physical activity is beneficial for cardiovascular health. Frequent exercise is robustly associated with a decrease in cardiovascular mortality as well as the risk of developing cardiovascular disease. Physically active individuals have lower blood pressure, higher insulin sensitivity, and a more favorable plasma lipoprotein profile. Animal models of exercise show that repeated physical activity suppresses atherogenesis and increases the availability of vasodilatory mediators such as nitric oxide. Exercise has also been found to have beneficial effects on the heart. Acutely, exercise increases cardiac output and blood pressure, but individuals adapted to exercise show lower resting heart rate and cardiac hypertrophy. Both cardiac and vascular changes have been linked to a variety of changes in tissue metabolism and signaling, although our understanding of the contribution of the underlying mechanisms remains incomplete. Even though moderate levels of exercise have been found to be consistently associated with a reduction in cardiovascular disease risk, there is evidence to suggest that continuously high levels of exercise (e.g., marathon running) could have detrimental effects on cardiovascular health. Nevertheless, a specific dose response relationship between the extent and duration of exercise and the reduction in cardiovascular disease risk and mortality remains unclear. Further studies are needed to identify the mechanisms that impart cardiovascular benefits of exercise in order to develop more effective exercise regimens, test the interaction of exercise with diet, and develop pharmacological interventions for those unwilling or unable to exercise

Rigor Me This: What Are the Basic Criteria for a Rigorous, Transparent, and Reproducible Scientific Study?

Scientific advancement is predicated upon the ability of a novel discovery to be independently reproduced and substantiated by others. Despite this inherent necessity, the research community is awash in published studies that cannot be replicated resulting in widespread confusion within the field and waning trust from the general public. In many cases, irreproducibility is the unavoidable consequence of a study that is conducted without the appropriate degree of rigor, typified by fundamental flaws in approach, design, execution, analysis, interpretation, and reporting. Combatting the irreproducibility pandemic in preclinical research is of urgent concern and is the primary responsibility of individual investigators, however there are important roles to be played by institutions, journals, government entities, and funding agencies as well. Herein, we provide an updated review of established rigor criteria pertaining to both in vitro and in vivo studies compiled from multiple sources across the research enterprise and present a practical checklist as a straightforward reference guide. It is our hope that this review may serve as an approachable resource for early career and experienced investigators alike, as they strive to improve all aspects of their scientific endeavors

Collagen Type XIX Regulates Cardiac Extracellular Matrix Structure and Ventricular Function

The cardiac extracellular matrix plays essential roles in homeostasis and injury responses. Although the role of fibrillar collagens have been thoroughly documented, the functions of non-fibrillar collagen members remain underexplored. These include a distinct group of non-fibrillar collagens, termed, fibril-associated collagens with interrupted triple helices (FACITs). Recent reports of collagen type XIX (encoded by Col19a1) expression in adult heart and evidence of its enhanced expression in cardiac ischemia suggest important functions for this FACIT in cardiac ECM structure and function. Here, we examined the cellular source of collagen XIX in the adult murine heart and evaluated its involvement in ECM structure and ventricular function. Immunodetection of collagen XIX in fractionated cardiovascular cell lineages revealed fibroblasts and smooth muscle cells as the primary sources of collagen XIX in the heart. Based on echocardiographic and histologic analyses, Col19a1 null (Col19a1(N/N)) mice exhibited reduced systolic function, thinning of left ventricular walls, and increased cardiomyocyte cross-sectional areas—without gross changes in myocardial collagen content or basement membrane morphology. Col19a1(N/N) cardiac fibroblasts had augmented expression of several enzymes involved in the synthesis and stability of fibrillar collagens, including PLOD1 and LOX. Furthermore, second harmonic generation-imaged ECM derived from Col19a1(N/N) cardiac fibroblasts, and transmission electron micrographs of decellularized hearts from Col19a1(N/N) null animals, showed marked reductions in fibrillar collagen structural organization. Col19a1(N/N) mice also displayed enhanced phosphorylation of focal adhesion kinase (FAK), signifying de-repression of the FAK pathway—a critical mediator of cardiomyocyte hypertrophy. Collectively, we show that collagen XIX, which had a heretofore unknown role in the mammalian heart, participates in the regulation of cardiac structure and function—potentially through modulation of ECM fibrillar collagen structural organization. Further, these data suggest that this FACIT may modify ECM superstructure via acting at the level of the fibroblast to regulate their expression of collagen synthetic and stabilization enzymes

Regulation of microvascular function by voltage‐gated potassium channels: New tricks for an “ancient” dog

Arterial tone is tightly regulated by a variety of potassium (K+ ) permeable ion channels at the sarcolemma of vascular smooth muscle cells. In particular, several types of KV channels provide a significant hyperpolarizing influence and serve to oppose pressure and agonist-induced membrane depolarization to promote smooth muscle relaxation and augmentation of vascular diameter and blood flow. In recent years, a number of studies have underscored previously unknown roles for particular KV subunits, new modes of channel regulation, and distinct cellular functions for these channels during physiological and pathological conditions. In this overview, we highlight articles contained in this Special Topics Issue that focus on the latest, most exciting advancements in the field of KV channels in the microcirculation. The collection of articles aims to highlight important new discoveries and controversies in the field of vascular KV channels as well as to shed light on key questions that require additional investigation

Coronary microvascular Kv1 channels as regulatory sensors of intracellular pyridine nucleotide redox potential

Smooth muscle voltage-gated potassium (Kv) channels are important regulators of microvascular tone and tissue perfusion. Recent studies indicate that Kv1 channels represent a key component of the physiological coupling between coronary blood flow and myocardial oxygen demand. While the mechanisms by which metabolic changes in the heart are transduced to alter coronary Kv1 channel gating and promote vasodilation are unclear, a growing body of evidence underscores a pivotal role of Kv1 channels in sensing the cellular redox status. Here, we discuss current knowledge of mechanisms of Kv channel redox regulation with respect to pyridine nucleotide modulation of Kv1 function via ancillary Kvβ proteins as well as direct modulation of channel activity via reactive oxygen and nitrogen species. We identify areas of additional research to address the integration of regulatory processes under altered physiological and pathophysiological conditions that may reveal insights into novel treatment strategies for conditions in which the matching of coronary blood supply and myocardial oxygen demand is compromised

Predominant contribution of L-type Cav1.2 channel stimulation to impaired intracellular calcium and cerebral artery vasoconstriction in diabetic hyperglycemia.

Enhanced L-type Ca2+ channel (LTCC) activity in arterial myocytes contributes to vascular dysfunction during diabetes. Modulation of LTCC activity under hyperglycemic conditions could result from membrane potential-dependent and independent mechanisms. We have demonstrated that elevations in extracellular glucose (HG), similar to hyperglycemic conditions during diabetes, stimulate LTCC activity through phosphorylation of CaV1.2 at serine 1928. Prior studies have also shown that HG can suppress the activity of K+ channels in arterial myocytes, which may contribute to vasoconstriction via membrane depolarization. Here, we used a mathematical model of membrane and Ca2+ dynamics in arterial myocytes to predict the relative roles of LTCC and K+ channel activity in modulating global Ca2+ in response to HG. Our data revealed that abolishing LTCC potentiation normalizes [Ca2+]i, despite the concomitant reduction in K+ currents in response to HG. These results suggest that LTCC stimulation may be the primary mechanism underlying vasoconstriction during hyperglycemia