CYP-450 Epoxygenase Derived Epoxyeicosatrienoic Acid Contribute To Reversal of Heart Failure in Obesity-Induced Diabetic Cardiomyopathy via PGC-1α Activation

Abstract

We have previously shown that an Epoxyeicosatrienoic Acid (EET) -agonist has pleiotropic effects and reverses cardiomyopathy by decreasing inflammatory molecules and increasing antioxidant signaling. We hypothesized that administration of an EET agonist would increase Peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α), which controls mitochondrial function and induction of HO-1 and negatively regulates the expression of the proinflammatory adipokines CCN3/NOV in cardiac and pericardial tissues. This pathway would be expected to further improve left ventricular (LV) systolic function as well as increase insulin receptor phosphorylation. Measurement of the effect of an EET agonist on oxygen consumption, fractional shortening, blood glucose levels, thermogenic and mitochondrial signaling proteins was performed. Control obese mice developed signs of metabolic syndrome including insulin resistance, hypertension, inflammation, LV dysfunction, and increased NOV expression in pericardial adipose tissue. EET agonist intervention decreased pericardial adipose tissue expression of NOV, while normalized FS, increased PGC-1α, HO-1 levels, insulin receptor phosphorylation and improved mitochondrial function, theses beneficial effect were reversed by deletion of PGC-1α. These studies demonstrate that an EET agonist increases insulin receptor phosphorylation, mitochondrial and thermogenic gene expression, decreased cardiac and pericardial tissue NOV levels, and ameliorates cardiomyopathy in an obese mouse model of the metabolic syndrome.

Cardioprotective Heme Oxygenase‐1‐PGC1α Signaling in Epicardial Fat Attenuates Cardiovascular Risk in Humans as in Obese Mice

“…In the present report, we describe signaling pathways in the epicardial fat of patients with overweight or obesity and coronary disease that correspond to pathways that we have previously described in epicardial fat of an obese mouse model. In addition, we describe adverse signaling expression pathways in the epicardial fat of overweight humans with vascular disease that are significantly more prominent than those found in visceral fat, another observation in concert with that seen in our mouse model (9,11,12). This suggests that the accumulation of inflammatory cytokines and chemokines in epicardial fat has a significantly greater toxic effect on the heart than those emanating from visceral fat, both in humans and mice.…”

“…Cardiac function, measured by echocardiography and calculation of LV FS, was impaired (P < 0.05 in db/db mice when compared with lean mice). Mice (db/db) were administered an EET agonist, with an inducer of HO-1-PGC1α for 8 weeks, followed by measuring FS (as previously described) (10,11). As depicted in Figure 4G, FS was reduced (P < 0.05) in untreated obese mice, while the treated mice (EET agonist) exhibited improved heart function as measured by increased FS.…”

“…used to perform real-time PCR. Specific TaqMan Gene Expression Assay probes (Thermo Fisher Scientific, Waltham, Massachusetts) for mouse HO-1, PGC1α, NOV, mitofusin 2 (MFN2), tumor necrosis factor (TNF-α), IL4, PRDM16, adiponectin, and GAPDH were used as previously described (9,11…”

“…Induction of NOV increased adipose tissue deposition, enhanced cholesterol, and increased insulin resistance and sleep apnea (8). In particular, epicardial fat is a distinct source of adipokines, reactive oxygen species (ROS), and inflammatory cytokines, and it has been tied to significant cardiac remodeling because of a decrease in the levels of heme oxygenase 1 (HO-1) (9,10) and peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1-alpha (PGC1α) (11,12). HO-1 is regarded as the first line of defense against oxidative stress given that oxidative stress is a strong inducer of HO, which comprises both an inducible and a constitutive form (HO-1 and HO-2, respectively) and catalyzes the oxidative degradation of heme into iron, biliverdin, and carbon monoxide (CO).…”

“…An increase in HO-1 expression triggers an increase in heme degradation and in the production of CO and bilirubin, an antiapoptotic and an antioxidant respectively, both of which decrease cardiac remodeling (10,13,14). An increase in mouse epicardial fat deposition is associated with a decrease of HO-1 levels in fat and a resultant increase in ROS (9,11). Importantly, perturbations in the levels of HO-1 were shown to regulate mitochondrial biogenesis (15) and levels of mitochondria carriers and their function (16).…”