Abstract
We have previously shown that transient and repetitive ischemia-induced (RI) coronary collateral growth (CCG) was severely impaired in a metabolic syndrome rat model (JCR rat). Levels of 20-hydroxyeicosatetraeonic acid (20-HETE), a cytochrome (CYP)-derived arachidonic acid metabolite are greatly elevated in hypertensive animal models and loosely associated with obesity in humans, but its levels in metabolic syndrome, especially in cardiovascular tissues, as well as its possible involvement in the regulation of collateral growth are unknown. In rats, CYP4A1 is the major enzyme responsible for the production of 20-HETE. In this study, we demonstrated that cardiac CYP4A1 expression (RT-PCR, Western blot and immunohistochemistry) and 20-HETE levels were markedly (10-fold) elevated in JCR vs. Sprague-Dawly (SD) rats in response to RI. Importantly, administration of an antagonist of 20-HETE, 20-SOLA, completely restored CCG in JCR rats (collateral flow was 86±1% of that in the normal zone (JCR+SOLA) vs. 21±2% (JCR) vs. 84±5% (SD), p<0.05). We conclude that 20-HETE is an important modulator of CCG in the metabolic syndrome where its myocardial tissue levels are highly elevated.
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