Abstract
Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) exert well recognized vasodilatory, diuretic, and tubular fluid-electrolyte transport actions that are predictive of a hypotensive effect. The study sought to determine the improvement of hypertension and cardiac function by over-expressing CYP epoxygenases in vivo. Long-term expression of CYP102 F87V or CYP2J2 in spontaneously hypertensive rats (SHR) was mediated by using a type 8 recombinant adeno-associated virus (rAAV8) vector. Hemodynamics was measured by a millar microtransducer catheter, and atrial natriuretic peptide (ANP) mRNA levels were tested by real-time PCR. Results showed that urinary excretion of 14,15-EET was increased at 2 and 6 months following injection with rAAV-CYP102 F87V and rAAV-CYP2J2 compared with controls (p<0.05). During the course of the 6-month study, sytolic blood pressure significantly decreased in CYP epoxygenase-treated rats, but the CYP2J2 specific inhibitor C26 blocked rAAV-CYP2J2 induced-hypotension and increase in EET production. Cardiac output was improved by CYP-epoxygenase expression at 6 months (p<0.05). Furthermore, cardiac collagen content was reduced in CYP epoxygenase-treated rats. Atrial natriuretic peptide (ANP) mRNA levels were up-regulated 6- to 14-fold in the myocardium, and ANP expression was significantly increased in both myocardium and plasma in CYP epoxygenase-treated rats. However, EGF receptor antagonist AG1478 significantly attenuated the increase in the EET-induced expression of ANP in vitro. These data indicate that overexpression of CYP epoxygenases attenuates the development of hypertension and improves cardiac function in SHR, and that these effects may be mediated, at least in part, by ANP via activating EGF receptor.
- Atrial Natriuretic Peptide
- Cardiovascular Physiology
- Cytochrome P450 epoxygenase
- Hypertension
- epoxyeicosatrienoic acids
- heart
Footnotes
- Received February 22, 2010.
- Revision received May 23, 2010.
- Accepted May 24, 2010.
- The American Society for Pharmacology and Experimental Therapeutics