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)

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Summary

Introduction

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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