Abstract
Cardiovascular disease (CVD) is a global health concern. Vascular dysfunction is an aspect of CVD, and novel treatments targeting vascular physiology are necessary. In the endothelium, eNOS regulates vasodilation and mitochondrial function; both are disrupted in CVD. (–)-Epicatechin, a botanical compound known for its vasodilatory, eNOS, and mitochondrial-stimulating properties, is a potential therapy in those with CVD. We hypothesized that (–)-epicatechin would support eNOS activity and mitochondrial respiration, leading to improved vasoreactivity in a thermoneutral-derived rat model of vascular dysfunction. We housed Wistar rats at room temperature or in thermoneutral conditions for a total of 16 week and treated them with 1mg/kg body weight (–)-epicatechin for 15 day. Vasoreactivity, eNOS activity, and mitochondrial respiration were measured, in addition to the protein expression of upstream cellular signaling molecules including AMPK and CaMKII. We observed a significant improvement of vasodilation in those housed in thermoneutrality and treated with (–)-epicatechin (p < 0.05), as well as dampened mitochondrial respiration (p < 0.05). AMPK and CaMKIIα and β expression were lessened with (–)-epicatechin treatment in those housed at thermoneutrality (p < 0.05). The opposite was observed with animals housed at room temperature supplemented with (–)-epicatechin. These data illustrate a context-dependent vascular response to (–)-epicatechin, a candidate for CVD therapeutic development.
Highlights
Cardiovascular disease (CVD) is characterized as the leading cause of mortality in the United States [1]
Temperature, EPICAT, and time interacted in these data, near significance (p < 0.08, Table 1), with those in TN treated with EPICAT weighing more than those at room temperature (RT) after 16 week (Table 1)
Higher insulin concentrations were observed in animals treated with EPICAT as compared with those given the vehicle, with a greater impact on insulin concentrations in those animals housed at RT (p < 0.001, Table 1)
Summary
Cardiovascular disease (CVD) is characterized as the leading cause of mortality in the United States [1]. Vascular disease progression is associated with diminished vasoreactivity (dilation and constriction) and endothelial function including structural stiffness, increased tone, and regional mitochondrial abnormalities [2–5]. Of particular interest is the vasodilator enzyme endothelial nitric oxide synthase (eNOS), known to have lower activity in CVD [6]. ENOS modulates endothelial-driven vasoreactivity, calcium signaling associated with vascular relaxation, and smooth muscle cell proliferation, in tandem with mitochondrial function [7–12]. Targeting the support of mitochondria and eNOS activity in the vasculature may lead to novel and necessary therapeutics. Additional studies in endothelial cells showed that EPICAT activates NOS in both a calcium-dependent and -independent manner [19,20] and stimulates mitochondrial respiration by enhancing complexes I and II and citrate synthase activity via eNOS activation [21,22]
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