CYP2J2-Derived Epoxyeicosatrienoic Acids Suppress Endoplasmic Reticulum Stress in Heart Failure

Abstract

Prolonged endoplasmic reticulum (ER) stress causes apoptosis and is associated with heart failure. Whether CYP2J2 and its arachidonic acid metabolites [epoxyeicosatrienoic acids (EETs)] have a protective influence on ER stress and heart failure has not been studied. Assays of myocardial samples from patients with end-stage heart failure showed evidence of ER stress. Chronic infusion of isoproterenol (ISO) or angiotensin II (AngII) by osmotic mini-pump induced cardiac hypertrophy and heart failure in mice as evaluated by hemodynamic measurements and echocardiography. Interestingly, transgenic (Tr) mice with cardiomyocyte-specific CYP2J2 expression were protected against heart failure compared with wild-type mice. ISO or AngII administration induced ER stress and apoptosis, and increased levels of intracellular Ca 21 . These phenotypes were abolished by CYP2J2 overexpression in vivo or exogenous EETs treatment of cardiomyocytes in vitro. ISO or AngII reduced sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a) expression in hearts or isolated cardiomyocytes; however, loss of SERCA2a expression was prevented in CYP2J2 Tr hearts in vivo or in cardiomyocytes treated with EETs in vitro. The reduction of SERCA2a activity was concomitant with increased oxidation of SERCA2a. EETs reversed SERCA2a oxidation through increased expression of antioxidant enzymes and reduced reactive oxygen species levels. Tempol, a membrane-permeable radical scavenger, similarly decreased oxidized SERCA2a levels, restored SERCA2a activity, and markedly reduced ER stress response in the mice treated with ISO. In conclusion, CYP2J2-derived EETs suppress ER stress response in the heart and protect against cardiac failure by maintaining intracellular Ca 21 homeostasis and SERCA2a expression and activity.

Ophiopogonin D maintains Ca2+ homeostasis in rat cardiomyocytes in vitro by upregulating CYP2J3/EETs and suppressing ER stress

“…EETs have diverse biological effects within the cardiovascular system, and CYP2J3 overexpression has been used to study www.chinaphar.com You WT et al Acta Pharmacologica Sinica npg homeostasis. This idea is consistent with previous studies in which a CYP2J3 transgene maintained SERCA2a activity and intracellular Ca 2+ homeostasis in rats with heart failure [20] . We found that OPD increased the expression of the CYP2J3 mRNA and protein ( Figure 1) the up-regulated activity of the CYP2J3 gene may increase EET synthesis.…”

“…Specifically, EETs have been reported to possess antiarrhythmic [16] , anti-inflammatory [17] , anti-apoptotic [18] , and antioxidant [19] functions. Additionally, CYP2J3 overexpression and increased levels of EETs have been reported to decrease ER stress signaling and ER stress-mediated apoptosis in rats with heart failure by maintaining SERCA2a activity and intracellular Ca 2+ homeostasis [20] . Additionally, research indicates that decreased SERCA2a expression and activity are hallmarks of heart failure in both experimental animal models and patients [21] .…”

14,15-Epoxyeicosatrienoic Acid Suppresses Cigarette Smoke Extract-Induced Apoptosis in Lung Epithelial Cells by Inhibiting Endoplasmic Reticulum Stress

“…A number of studies have shown that EETs have anti-inflammatory, antioxidative and antiapoptotic activities [12][13][14][15][16]16. In addition, EETs can reduce ER stress signaling in liver, adipose and heart tissues [17,18]. CYP2J2 mRNA and protein have been detected in the human pulmonary epithelial cells, vascular endothelial cells, vascular smooth muscle cells and alveolar macrophages, either in vitro or in vivo , [11,19].…”

Danazol Inhibits Cytochrome P450 2J2 Activity in a Substrate-independent Manner

“…CYP2J2 is involved in the metabolism of arachidonic acid (Zeldin, 2001;Roman, 2002). It metabolizes arachidonic acid to epoxyeicosatrienoic acids, which play a role in homeostasis of the heart, lungs, and kidneys (Fleming, 2001;Kroetz and Zeldin, 2002;Smith et al, 2008;Feng et al, 2013;Wang et al, 2014). In addition to its endogenous role, CYP2J2 also metabolizes medications such as albendazole, astemizole, ebastine, and terfenadine (Matsumoto and Yamazoe, 2001;Hashizume et al, 2002;Matsumoto et al, 2002;Lafite et al, 2006;Liu et al, 2006;Lee et al, 2012;Ren et al, 2013;Wu et al, 2013b).…”