Hypercholesterolemia and Hypertension Have Synergistic Deleterious Effects on Coronary Endothelial Function

Abstract

Objective-Coronary endothelial dysfunction is associated with an increase in cardiac events. Hypercholesterolemia (HC) and hypertension (HT) are both associated with endothelial dysfunction, and their coexistence is associated with an increased incidence of cardiac events in epidemiological studies. However, pathogenic mechanisms are poorly understood. Here we studied the effects of coexisting HC and HT on coronary endothelial function. Methods and Results-Four groups of pigs were studied after 12 weeks of a normal diet (nϭ9), a 2% HC diet (nϭ9), HT (achieved by unilateral renal artery stenosis, nϭ8), or HCϩHT (nϭ6). Coronary endothelial function was tested, in epicardial arteries and arterioles, by using organ chamber techniques. Oxidative stress was measured in coronary artery tissue. Vasodilatory response to bradykinin and calcium ionophore was significantly impaired in animals with HCϩHT compared with each risk factor alone (PϽ0.05 for both). In animals with coexistent HC and HT, the increase in oxidative stress was more pronounced compared with each risk factor alone (PϽ0.05). Furthermore, chronic antioxidant supplementation significantly improved coronary artery vasoreactivity. Conclusions-These results suggest that HC and HT have a synergistic deleterious effect on coronary endothelial function, associated with increased oxidative stress. This interaction may contribute to the increased incidence of coronary heart disease and cardiac events seen when HC and HT coexist. Key Words: animal models Ⅲ coronary circulation Ⅲ oxidant stress Ⅲ risk factors A therosclerosis-related coronary disease, in its early stages, is characterized by coronary endothelial dysfunction, potentially leading to an increased incidence of cardiac events. 1 Hypercholesterolemia (HC) and hypertension (HT) are major risk factors for atherosclerosis, and their combination is associated with a yet greater increase in the incidence of cardiac events. 2 Thus, it becomes increasingly important to understand the pathogenic mechanisms of their interaction. Individually, both diet-induced HC 3 and HT 4,5 have been associated with abnormalities in coronary endothelial function. Although the effect of each risk factor has been studied individually, whether their coexistence has a synergistic deleterious effect on coronary endothelial function remains poorly understood.One of the mechanisms that might be activated in both HC 6,7 and HT 8 and might hinder coronary vascular function is a shift in scavenging activity and redox status, a state known as increased oxidative stress. Increased vascular oxidative stress can be characterized by increased production of reactive oxygen species (ROS) and pro-oxidant reactions 8,9 and decreased levels of endogenous antioxidants 7 and endogenous radical scavenger systems, 7 as well as an increase in oxidazibility, which might also impair vascular function. 10,11 Furthermore, increased oxidative stress can also have deleterious effects on other pathways, such as the nitric oxide (NO) pathway. 12,13 Thus, these...

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