Overexpression of Cytochrome P450 Epoxygenases Prevents Development of Hypertension in Spontaneously Hypertensive Rats by Enhancing Atrial Natriuretic Peptide

Abstract

Cytochrome P450 (P450)-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 overexpressing P450 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 Instruments, Inc. (Houston, TX) microtransducer catheter, and atrial natriuretic peptide (ANP) mRNA levels were tested by real-time polymerase chain reaction. Results showed that urinary excretion of 14,15-EET was increased at 2 and 6 months after injection with rAAV-CYP102 F87V and rAAV-CYP2J2 compared with controls (p Ͻ 0.05). During the course of the 6-month study, systolic blood pressure significantly decreased in P450 epoxygenase-treated rats, but the CYP2J2-specific inhibitor C26 blocked rAAV-CYP2J2-induced hypotension and the increase in EET production. Cardiac output was improved by P450 epoxygenase expression at 6 months (p Ͻ 0.05). Furthermore, cardiac collagen content was reduced in P450 epoxygenase-treated rats. 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 P450 epoxygenase-treated rats. However, epidermal growth factor (EGF) receptor antagonist 4-(3Ј-chloroanilino)-6,7-dimethoxyquinazoline (AG-1478) significantly attenuated the increase in the EET-induced expression of ANP in vitro. These data indicate that overexpression of P450 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.

Epoxyeicosatrienoic acids protect rat hearts against tumor necrosis factor-α-induced injury

“…In vivo experiments showed that CYP2J2 overexpression attenuates production of VCAM, E-selectin, IL-1 ␤ , and IL-6 while enhancing production of the anti-infl ammatory cytokine IL-10. In addition, CYP2J2 gene delivery via intravenous injection signifi cantly increased CYP2J2 expression in vivo in most organs, mainly aorta, heart, liver, and kidney ( 3,5,6,36,37 ), which may also explain some effects of heart protection. These results support the view that CYP2J2-derived EETs protect the heart via their antiinfl ammatory, antiapoptotic, and prosurvival effects.…”

Functional studies of N‐terminally modified CYP2J2 epoxygenase in model lipid bilayers

“…In humans, CYP2J2 is highly expressed in cardiac myocytes and the endothelium of coronary arteries where it plays significant roles in cardiovascular diseases and inflammation. [4][5][6][7] This enzyme Abbreviations: CPR, cytochrome P450 reductase; CYP2J2, cytochrome P450 2J2; ND, Nanodiscs; POPC, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine; POPS, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoserine.…”

CYP 2J2 and its metabolites (epoxyeicosatrienoic acids) attenuate cardiac hypertrophy by activating AMPK α2 and enhancing nuclear translocation of Akt1

“…Our previous study demonstrated that EETs and CYP epoxygenases markedly activate Akt and inhibit cardiac hypertrophy (Xiao et al ., 2010). To further understand this controversial phenomenon, we investigated whether 11,12‐EET‐induced ANP expression was mediated by the activation of Akt in cardiac hypertrophy and whether EETs enhanced the nuclear translocation of Akt.…”

“…There are accumulating evidences that EETs (Althurwi et al ., 2013; He et al ., 2015) might also protect against cardiac hypertrophy (Ai et al ., 2009). Overexpression of CYP epoxygenases improved cardiac function in spontaneously hypertensive rats, and these effects may have been mediated, at least in part, by the atrial natriuretic peptide (ANP) activation of the epidermal growth factor (EGF) receptor (Xiao et al ., 2010). However, the detailed molecular mechanisms by which EETs protect against cardiac hypertrophy or heart failure remain unclear.…”