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.

E-cigarette use has surged, but the long-term health effects remain unknown. E-cigarette aerosols containing nicotine and acrolein, a combustion and e-cigarette byproduct, may impair cardiac electrophysiology through autonomic imbalance. Here we show in mouse electrocardiograms that acute inhalation of e-cigarette aerosols disturbs cardiac conduction, in part through parasympathetic modulation. We demonstrate that, similar to acrolein or combustible cigarette smoke, aerosols from e-cigarette solvents (vegetable glycerin and propylene glycol) induce bradycardia, bradyarrhythmias, and elevations in heart rate variability during inhalation exposure, with inverse post-exposure effects. These effects are slighter with tobacco- or menthol-flavored aerosols containing nicotine, and in female mice. Yet, menthol-flavored and PG aerosols also increase ventricular arrhythmias and augment early ventricular repolarization (J amplitude), while menthol uniquely alters atrial and atrioventricular conduction. Exposure to e-cigarette aerosols from vegetable glycerin and its byproduct, acrolein, diminish heart rate and early repolarization. The pro-arrhythmic effects of solvent aerosols on ventricular repolarization and heart rate variability depend partly on parasympathetic modulation, whereas ventricular arrhythmias positively associate with early repolarization dependent on the presence of nicotine. Our study indicates that chemical constituents of e-cigarettes could contribute to cardiac risk by provoking pro-arrhythmic changes and stimulating autonomic reflexes.

Elevated blood glucose (hyperglycemia) is a hallmark metabolic abnormality in diabetes. Hyperglycemia is associated with protein kinase A–dependent (PKA-dependent) stimulation of L-type Ca²⁺ channels in arterial myocytes resulting in increased vasoconstriction. However, the mechanisms by which glucose activates PKA remain unclear. Here, we showed that elevating extracellular glucose stimulates cAMP production in arterial myocytes, and that this was specifically dependent on adenylyl cyclase 5 (AC5) activity. Super-resolution imaging suggested nanometer proximity between subpopulations of AC5 and the L-type Ca²⁺ channel pore-forming subunit Ca_V1.2. In vitro, in silico, ex vivo, and in vivo experiments revealed that this close association is critical for stimulation of L-type Ca²⁺ channels in arterial myocytes and increased myogenic tone upon acute hyperglycemia. This pathway supported the increase in L-type Ca²⁺ channel activity and myogenic tone in 2 animal models of diabetes. Our collective findings demonstrate a unique role for AC5 in PKA-dependent modulation of L-type Ca²⁺ channel activity and vascular reactivity during acute hyperglycemia and diabetes.

Elevated glucose increases vascular reactivity by promoting L-type Ca_V1.2 channel (LTCC) activity by protein kinase A (PKA). Yet, how glucose activates PKA is unknown. We hypothesized that a G_s-coupled P2Y receptor is an upstream activator of PKA mediating LTCC potentiation during diabetic hyperglycemia. Experiments in apyrase-treated cells suggested involvement of a P2Y receptor underlying the glucose effects on LTTCs. Using human tissue, expression for P2Y₁₁, the only G_s-coupled P2Y receptor, was detected in nanometer proximity to Ca_V1.2 and PKA. FRET-based experiments revealed that the selective P2Y₁₁ agonist NF546 and elevated glucose stimulate cAMP production resulting in enhanced PKA-dependent LTCC activity. These changes were blocked by the selective P2Y₁₁ inhibitor NF340. Comparable results were observed in mouse tissue, suggesting that a P2Y₁₁-like receptor is mediating the glucose response in these cells. These findings established a key role for P2Y₁₁ in regulating PKA-dependent LTCC function and vascular reactivity during diabetic hyperglycemia.