Early Changes in Cytochrome P450s and Their Associated Arachidonic Acid Metabolites Play a Crucial Role in the Initiation of Cardiac Hypertrophy Induced by Isoproterenol

Abstract

Cytochrome P450 enzymes (P450s), along with their cardioprotective metabolites the epoxyeicosatrienoic acids (EETs) and cardiotoxic metabolite 20-hydroxyeicosatetraeonic acid (20-HETE), were found to be altered in cardiac hypertrophy; however, it is unclear whether these changes are causal or epiphenomenon. Therefore, we hypothesized that P450s and their metabolites play a crucial role in the initiation of cardiac hypertrophy. To test our hypothesis, rats and RL-14 cells were treated with the hypertrophic agonist isoproterenol for different time periods. Thereafter, in vivo heart function and wall thickness were assessed using echocardiography. Moreover, the role of P450 epoxygenases, v-hydroxylases, and soluble epoxide hydrolase (sEH) were determined at mRNA, protein, and activity levels using real-time polymerase chain reaction, Western blot, and liquid chromatography-mass spectrometry, respectively. Our results show that in vivo and in vitro hypertrophy was initiated after 72 hours and 6 hours of isoproterenol treatment, respectively. Studies performed at the prehypertrophy phase showed a significant decrease in P450 epoxygenases along with a significant induction of sEH activity. Consequently, lower EET and higher dihydroxyeicosatrienoic acid levels were observed during this phase. However, significant increases in P450 v-hydroxylase along with its associated metabolite, 20-HETE, were detected only in vivo. Interestingly, increasing EET levels by P450 epoxygenase induction, sEH inhibition, or exogenous administration of EET prevented the initiation of cardiac hypertrophy through a nuclear factor-kB-mediated mechanism. Taken together, these findings reveal a crucial role of P450 epoxygenases and EETs in the development of cardiac hypertrophy, which could uncover novel targets for prevention of heart failure at early stages.

20-HETE in the regulation of vascular and cardiac function

“…CYP4A and 4F are similarly upregulated in patients and animal models of mal-adaptive cardiac hypertrophy associated with heart failure. CYP4A and 4F were increased in isopreteranol-induced cardiac hypertrophy in rats (Althurwi, Maayah, Elshenawy, & El-Kadi, 2015; Zordoky, Aboutabl, & El-Kadi, 2008). 20-HETE levels were also shown to be elevated in Ang II-induced hypertrophy (Elkhatali, El-Sherbeni, Elshenawy, Abdelhamid, & El-Kadi, 2015).…”

Cymbopogon Proximus Essential Oil Protects Rats against Isoproterenol-Induced Cardiac Hypertrophy and Fibrosis

“…The fourth group received a daily IP injection of both isoproterenol (5 mg/kg/d) and C. proximus oil (800 µL/kg/d). The administration of oil was started four days prior to the isoproterenol administration and continued concurrently thereafter for an additional 3 d. The dose and period of isoproterenol administration were selected based on our previous study [8]. All animal groups were euthanized 24 h after the last dose of treatment.…”

“…The prognosis for patients with HF remains poor with 50% of patients dying within five years of diagnosis [6]. Cardiac hypertrophy, a thickening of the heart wall in response to increased cardiac stress, occurs early on in the CVD continuum and is considered as a compensatory response that permits normal cardiovascular function at rest [7,8]. However, prolonged hypertrophy is now recognized as a credible surrogate endpoint of HF and a major risk factor for heart disease, including coronary artery disease (CAD), arrhythmia, and hypertension [9].…”

Molecular mechanisms in differentiated thyroid cancer

“…In both patients and animal models, enzymes of the CYP4A and 4F families are upregulated in association with maladaptive cardiac hypertrophy associated with heart failure (96). For example, the expression of CYP4A11 mRNA is elevated in hypertrophic human hearts (169) and the expression of CYP4A3 and 4F4, and the production of 20-HETE was found to be elevated in isoproterenol-induced cardiac hypertrophy in rats (130, 355). Treatment of SD rats with fenofibrate was found to decrease CYP4A3 cardiac gene expression and protein levels and 20-HETE formation cardiac microsomes (356).…”

“…This has been the subject of several recent and definitive reviews (11, 26, 117–121). The role of 20-HETE in ischemic and hemorrhagic stroke (122–125), acute renal failure (126, 127), toxemia of pregnancy (128), hepatorenal syndrome (129), vascular restenosis (23), angiogenesis (24), cardiac hypertrophy (130) and ischemia reperfusion (IR) injury (131), as well as shock (132, 133) is less well known and has received little attention in the literature. This review will focus on the emerging pathogenic role of 20-HETE as an important mediator in vascular dysfunction, inflammation in a variety of diseases.…”