Cyp2c44 Gene Disruption Is Associated With Increased Hematopoietic Stem Cells: Implication in Chronic Hypoxia-induced Pulmonary Hypertension

We have recently demonstrated that disruption of the murine cytochrome P450 2c44 gene exacerbates chronic hypoxia-induced pulmonary artery remodeling and hypertension in mice. Subsequently, we serendipitously found that Cyp2c44 gene disruption also increases hematopoietic stem cell (HSC) number in bone marrow and blood. Therefore, the objective of this study was to investigate whether Cyp2c44 disruption regulates HSC phenotype and whether increases in differentiated HSCs contribute to chronic hypoxia-induced remodeling of pulmonary arteries. Our findings demonstrated that lack of a CYP2C44 epoxygenase, which produces epoxyeicosatrienoic acids and hydroxyeicosatetraenoic acids, increases: 1] HSC (CD34+, CD117+, and CD133+) numbers, 2] proangiogenic (CD34+, CD133+, CD34+, CD117+, CD133+) cells, and 3] immunogenic/inflammatory (CD34+, CD11b+, CD133+, CD11b+, F4/80+, CD11b+, and F4/80+ CD11b+) monocytes and macrophages, in bone morrow and blood as compared to wild type mice. Furthermore, we identified increased CD133+ and von Willebrand factor positive cells, which are derived from proangiogenic stem cells, in remodeled and occluded pulmonary arteries of CYP2C44-deficient mice exposed to chronic hypoxia. In conclusion, our results demonstrated that CYP2C44-derived lipid mediators played a critical role in regulating HSCs phenotype, because disruption of Cyp2c44 gene increased differentiated HSCs that potentially contributed to chronic hypoxia-induced pulmonary artery remodeling and occlusion

EET Intervention on Wnt1, NOV, and HO-1 Signaling Prevents Obesity-induced Cardiomyopathy in Obese Mice

We have previously reported that epoxyeicosatrienoic acid (EET) has multiple beneficial effects on vascular function; in addition to its antiapoptotic action, it increases insulin sensitivity and inhibits inflammation. To uncover the signaling mechanisms by which EET reduces cardiomyopathy, we hypothesized that EET infusion might ameliorate obesity-induced cardiomyopathy by improving heme oxygenase (HO)-1, Wnt1, thermogenic gene levels, and mitochondrial integrity in cardiac tissues and improved pericardial fat phenotype. EET reduced levels of fasting blood glucose and proinflammatory adipokines, including nephroblastoma overexpressed (NOV) signaling, while increasing echocardiographic fractional shortening and O2 consumption. Of interest, we also noted a marked improvement in mitochondrial integrity, thermogenic genes, and Wnt 1 and HO-1 signaling mechanisms. Knockout of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) in EET-treated mice resulted in a reversal of these beneficial effects including a decrease in myocardial Wnt1 and HO-1 expression and an increase in NOV. To further elucidate the effects of EET on pericardial adipose tissues, we observed EET treatment increases in adiponectin, PGC-1alpha, phospho-AMP-activated protein kinase, insulin receptor phosphorylation, and thermogenic genes, resulting in a browning pericardial adipose phenotype under high-fat diets. Collectively, these experiments demonstrate that an EET agonist increased Wnt1 and HO-1 signaling while decreasing NOV pathways and the progression of cardiomyopathy. Furthermore, this report presents a portal into potential therapeutic approaches for the treatment of heart failure and metabolic syndrome.NEW & NOTEWORTHY The mechanism by which EET acts on obesity-induced cardiomyopathy is unknown. Here, we describe a previously unrecognized function of EET infusion that inhibits nephroblastoma overexpressed (NOV) levels and activates Wnt1, hence identifying NOV inhibition and enhanced Wnt1 expression as novel pharmacological targets for the prevention and treatment of cardiomyopathy and heart failure.Listen to this article\u27s corresponding podcast at http://ajpheart.physiology.org/content/early/2017/05/31/ajpheart.00093.2017

Inhibition of soluble epoxide hydrolase increases coronary perfusion in mice.

Roles of soluble epoxide hydrolase (sEH), the enzyme responsible for hydrolysis of epoxyeicosatrienoic acids (EETs) to their diols (DHETs), in the coronary circulation and cardiac function remain unknown. We tested the hypothesis that compromising EET hydrolysis/degradation, via sEH deficiency, lowers the coronary resistance to promote cardiac perfusion and function. Hearts were isolated from wild type (WT), sEH knockout (KO) mice and WT mice chronically treated with t-TUCB (sEH inhibitor), and perfused with constant flow at different pre-loads. Compared to WT controls, sEH-deficient hearts required significantly greater basal coronary flow to maintain the perfusion pressure at 100 mmHg and exhibited a greater reduction in vascular resistance during tension-induced heart work, implying a better coronary perfusion during cardiac performance. Cardiac contractility, characterized by developed tension in response to changes in preload, was potentially increased in sEH-KO hearts, manifested by an enlarged magnitude at each step-wise increase in end-diastolic to peak-systolic tension. 14,15-EEZE (EET antagonist) prevented the adaptation of coronary circulation in sEH null hearts whereas responses in WT hearts were sensitive to the inhibition of NO. Cardiac expression of EET synthases (CYP2J2/2C29) was comparable in both genotypic mice whereas, levels of 14,15-, 11,12- and 8,9-EETs were significantly higher in sEH-KO hearts, accompanied with lower levels of DHETs. In conclusion, the elevation of cardiac EETs, as a function of sEH deficiency, plays key roles in the adaptation of coronary flow and cardiac function