CYP2J2 metabolites, epoxyeicosatrienoic acids, attenuate Ang II-induced cardiac fibrotic response by targeting Gα12/13

Abstract

The arachidonic acid-cytochrome P450 2J2-epoxyeicosatrienoic acid (AA-CYP2J2-EET) metabolic pathway has been identified to be protective in the cardiovascular system. This study explored the effects of the AA-CYP2J2-EET metabolic pathway on cardiac fibrosis from the perspective of cardiac fibroblasts and underlying mechanisms. In in vivo studies, 8-week-old male CYP2J2 transgenic mice (aMHC-CYP2J2-Tr) and littermates were infused with angiotensin II (Ang II) or saline for 2 weeks. Results showed that CYP2J2 overexpression increased EET production. Meanwhile, impairment of cardiac function and fibrotic response were attenuated by CYP2J2 overexpression. The effects of CYP2J2 were associated with reduced activation of the α subunits of G12 family G proteins (Gα)/RhoA/Rho kinase (ROCK) cascade and elevation of the NO/cyclic guanosine monophosphate (cGMP) level in cardiac tissue. In in vitro studies, cardiac fibroblast activation, proliferation, migration, and collagen production induced by Ang II were associated with activation of the Gα/RhoA/ROCK pathway, which was inhibited by exogenous 11,12-EET. Moreover, silencing of Gα or RhoA exerted similar effects as 11,12-EET. Furthermore, inhibitory effects of 11,12-EET on Gα were blocked by NO/cGMP pathway inhibitors. Our findings indicate that enhancement of the AA-CYP2J2-EET metabolic pathway by CYP2J2 overexpression attenuates Ang II-induced cardiac dysfunction and fibrosis by reducing the fibrotic response of cardiac fibroblasts by targeting the Gα/RhoA/ROCK pathway via NO/cGMP signaling.

COX‐2/sEH dual inhibitor PTUPB alleviates bleomycin‐induced pulmonary fibrosis in mice via inhibiting senescence

“…There are three primary enzymatic pathways producing eicosanoid metabolites, including the cyclooxygenase (COX) pathway, the lipoxygenase (LOX) pathway, and the cytochrome P450 (CYP) pathway . The CYP pathway of ARA metabolism generates epoxyeicosatrienoic acids (EETs), which have anti‐inflammatory and antifibrotic biological activities . However, EETs are rapidly metabolized by soluble epoxide hydrolase (sEH) .…”

Effects of Three-Month Feeding High Fat Diets with Different Fatty Acid Composition on Myocardial Proteome in Mice

“…Accumulating evidence suggests that EETs display a broad spectrum of cardioprotective effects in the heart, including the impact on cardiac vasculature, heart fibroblasts and cardiomyocytes [ 33 ]. Recently, EETs have also been shown to cause coronary artery dilation, resulting in improved coronary blood flow [ 34 ], and to markedly limit collagen deposition [ 35 ]. A direct influence of EETs on cardiac myocytes have also been proposed, including the improvement of mitochondrial function, protection from angiotensin II-induced cardiac hypertrophy [ 36 , 37 ] and anti-arrhythmic effects [ 32 ].…”

Gastrin stimulates pancreatic cancer cell directional migration by activating the Gα12/13–RhoA–ROCK signaling pathway

“…The heterotrimeric G proteins Gα12 and Gα13 are widely expressed in human tissues, have been described as RhoA activators via RH-containing RhoGEFs, and can promote actin stress fiber formation and focal adhesion assembly 22 , 23 . Gα12/13 have consistently been demonstrated to play a key role in oncogenic transformation in multiple cancers, such as prostate cancer, breast cancer, and cervical cancer 44 - 46 , while its role in pancreatic cancer is largely unknown.…”