Metformin decreased myocardial fibrosis and apoptosis in hyperhomocysteinemia -induced cardiac hypertrophy.

BACKGROUND: Hyperhomocysteinemia (HHcy) is one of the major risk factors of cardiovascular diseases. Metformin acts as a cardioprotective role in several cardiovascular diseases, including ischemia/reperfusion, atherosclerosis, and myocardial infarction. However, whether metformin protects against HHcy-induced cardiac hypertrophy is unclear. METHODS AND RESULTS: HHcy model was established in C57BL/6 mice with high L-methionine (L-MET) diet for 12 weeks. AC16 cells were exposed to homocysteine (Hcy) and then intervened with different concentrations of metformin in in vitro studies. The results showed that HHcy was able to induce cardiac hypertrophy, and metformin could abrogate this effect. HHcy increased the fibrosis area and induced apoptosis in the myocardium, whereas metformin could reverse the detrimental effects above. TUNEL assay showed that metformin was able to decrease Hcy-induced apoptosis in AC16 cells. Moreover, western blotting assay revealed that metformin could decrease Hcy-induced expression of Bax and cleaved caspase3, and increase the expression of Bcl-2. CONCLUSIONS: This study demonstrates that metformin is able to attenuate HHcy-induced cardiac hypertrophy by decreasing myocardial fibrosis and apoptosis.

The effects of endothelium-specific CYP2J2 overexpression on the attenuation of retinal ganglion cell apoptosis in a glaucoma rat model.

Glaucoma is a leading cause of irreversible blindness worldwide. Vascular factors play a substantial role in the pathogenesis of glaucoma. Expressed in the vascular endothelium, cytochrome P450 (CYP) 2J2 is one of the CYP epoxygenases that metabolize arachidonic acid to produce epoxyeicosatrienoic acids and exert pleiotropic protective effects on the vasculature. In the present study, we investigated whether endothelium-specific overexpression of CYP2J2 (tie2-CYP2J2-Tr) protects against retinal ganglion cell (RGC) loss induced by glaucoma and in what way retinal vessels are involved in this process. We used a glaucoma model of retinal ischemia-reperfusion (I/R) injury in rats and found that endothelium-specific overexpression of CYP2J2 attenuated RGC loss induced by retinal I/R. Moreover, retinal I/R triggered retinal vascular senescence, indicated by up-regulated senescence-related proteins p53, p16, and ß-galactosidase activity. The senescent endothelial cells resulted in pericyte loss and increased endothelial secretion of matrix metallopeptidase 9, which further contributed to RGC loss. CYP2J2 overexpression alleviated vascular senescence, pericyte loss, and matrix metallopeptidase 9 secretion. CYP2J2 suppressed endothelial senescence by down-regulating senescence-associated proteins p53 and p16. These 2 proteins were positively regulated by microRNA-128-3p, which was inhibited by CYP2J2. These results suggest that CYP2J2 protects against endothelial senescence and RGC loss in glaucoma, a discovery that may lead to the development of a potential treatment strategy for glaucoma.-Huang, J., Zhao, Q., Li, M., Duan, Q., Zhao, Y., Zhang, H. The effects of endothelium-specific CYP2J2 overexpression on the attenuation of retinal ganglion cell apoptosis in a glaucoma rat model.

Integrated analyses of lncRNAs microarray profiles and mRNA-lncRNA coexpression in smooth muscle cells under hypoxic and normoxic conditions.

Hypoxia may cause abnormal proliferation and migration of the vascular smooth muscle cells (VSMCs) from the media to the intima. This contributes to vessel narrowing and accelerates the process of atherosclerosis. The association of the aberrant expression of long noncoding RNAs (lncRNAs) with the development and progression of atherosclerosis is well known; however, it is not well investigated in hypoxic VSMCs. Using a microarray approach, we identified 1056 and 2804 differentially expressed lncRNAs and mRNAs, respectively, in hypoxic and normoxic mouse aorta smooth muscle (MOVAS) cells. Of them, we randomly chose several lncRNAs and validated the microarray data using the quantitative PCR (qPCR) assay. Advanced bioinformatics analyses indicated that the up-regulated mRNAs were mainly involved in inflammatory responses, lipid metabolism, clearance of amyloid-ß peptide, citrate cycle (TCA cycle), TGF-ß signaling, and chemokine signaling. The down-regulated mRNAs were mainly involved in the apoptosis pathway, glycerolipid metabolism, Wnt signaling pathway, and MAPK signaling pathway. The constructed coexpression network indicated interactions between 87 lncRNAs and ten mRNAs. In addition, we demonstrated that the silence of lncRNA NONMMUT002434 expression could abrogate the migration and proliferation of smooth muscle cells dramatically. Our data provide comprehensive evidence on the differential expression of lncRNAs and mRNAs in hypoxic MOVAS cells, which may be valuable biomarkers for atherosclerotic diseases, and thereby facilitating diagnosis of atherosclerosis.

Endothelium-specific CYP2J2 overexpression improves cardiac dysfunction by promoting angiogenesis via Jagged1/Notch1 signaling.

BACKGROUND: Myocardial infarction (MI) contributes to the development of cardiac remodeling and heart failure. Insufficient post-MI myocardial angiogenesis has been identified as a non-negligible event which precipitates heart failure progression. Previous studies reported that cytochrome P450 epoxygenase and its metabolites exerted beneficial effects on cardiovascular diseases. However, the role of cytochrome P450 2J2 (CYP2J2) in post-MI heart failure is incompletely understood. METHODS AND RESULTS: First, western blot and real-time PCR analyses showed that CYP2J2 expression increased clearly in patients with acute MI and old MI, compared to control. Second, echocardiography and histological studies showed that transgenic (TG) rats had relatively preserved cardiac function, as well as attenuated remodeling, and reduced scar formation, compared to the wild-type (WT) littermates after MI eight weeks. Importantly, the cardioprotective effect induced by CYP2J2 overexpression was abrogated by VEGFR2 inhibitor-cediranib. More intriguingly, positron emission computed Tomography (PET) analyses showed that TG rats displayed better myocardial perfusion than WT rats. We found that these effects were linked to increasing circulating EETs and enhancing myocardial angiogenesis. Additionally, in vitro study demonstrated that 11, 12-epoxyeicosatrienoic acid (11, 12-EET) induced more robust tube formation and markedly increased VEGF-A and bFGF expression in hypoxia and normoxia. Finally, western blot analyses uncovered that CYP2J2 and 11, 12-EET promoted angiogenesis via the Jagged1/Notch1 signaling pathway. CONCLUSIONS: Our findings demonstrate that CYP2J2 improves cardiac function by increasing the concentration of circulating EETs, and boosting angiogenesis via the Jagged1/Notch1 signaling pathway in MI-induced heart failure.