Obesity is growing rapidly worldwide due to consumption of westernized diet and lack of exercise. Obesity is one of the major risk factors of hypertension. The novel histone deacetylase (HDAC) inhibitor CG200745 was originally developed to treat various cancers. Previous studies showed that CG200745 attenuated hypertension through inhibition of cardiac hypertrophy and fibrosis in deoxycorticosterone acetate-induced hypertensive rat. The purpose of this study is to investigate the role and underlying mechanism of CG200745 in high-fat diet (HFD)-induced hypertension. Nine-week old C57BL/6 mice were fed a normal diet (ND) or HFD for 17 weeks. Each group of mice was treated with vehicle or CG200745 by intraperitoneal injection for 9 days. HFD group showed higher body weight, blood pressure (BP), HDAC activities, angiotensinogen and renin expressions in kidney, angiotensin-converting enzyme (ACE) expression in the lung, serum angiotensin II (Ang II) concentration, and myosin light chain 20 (MLC 20) phosphorylation in mesenteric artery compared with ND group. CG200745 lowered BP, HDAC activity, renin and angiotensinogen in the kidney, ACE in the lung, serum Ang II level, and phosphorylation of MLC 20 in HFD group. In conclusion, CG200745 ameliorated HFD-induced hypertension through inhibition of HDAC/Ang II/vascular contraction axis. Our results offer CG200745 as a novel therapeutic option for HFD-induced hypertension.
Hydrogen sulfide (H 2 S) is an endogenous gaseous antioxidant and antihypertensive molecule produced during the homocysteine metabolism. MsrA (methionine sulfoxide reductase A) enables the metabolism of homocysteine by reducing methionine sulfoxide to methionine. Although HDAC (histone deacetylase) inhibition has been reported to show blood pressure lowering effects, their effects on endogenous H 2 S production are largely unknown. Here, we assessed the relevance of MsrA in high-fat diet (HFD)-induced hypertension and the effect of HDAC inhibition on MsrA expression, H 2 S production, and hypertension. Male C57BL/6 mice were fed a normal diet or HFD. HFD increased blood pressure and activities of HDAC3 and 6 but downregulated MsrA in the mesenteric arteries and the serum H 2 S level. HFD upregulated 4 hydroxynonenal, TNF (tumor necrosis factor)-α, and IL (interleukin)-6, and vasocontractile proteins. The histone H3 acetylation of the MsrA promoter was decreased by HFD. In hypertensive HFD-fed mice, administration of the HDAC inhibitor CG200745 lowered blood pressure and increased serum H 2 S level. CG200745 increased acetylation of histone H3 and MsrA levels in the mesenteric arteries while downregulating oxidative stress, inflammation, and vasocontractile proteins. Silencing of MsrA in the vascular smooth muscle cells recapitulated HFD-induced in vivo hypertensive effects. CG200745 increased the histone H3 acetylation of the MsrA promoter, MsrA expression, and H 2 S production in vascular smooth muscle cells, supporting the in vivo results. Collectively, HFD-induced downregulation of MsrA plays a pivotal role in HFD-induced hypertension by reducing H 2 S levels. MsrA expression is epigenetically regulated by HDAC inhibitors, providing HDAC inhibitors as a therapeutic option and MsrA and H 2 S as novel therapeutic targets.
Mitochondrial NADP + -dependent isocitrate dehydrogenase 2 (IDH2) produces NADPH, which is known to inhibit mitochondrial oxidative stress. Ureteral obstruction induces kidney inflammation and fibrosis via oxidative stress. Here, we investigated the role and underlying mechanism of IDH2 in unilateral ureteral obstruction (UUO)-induced kidney inflammation using IDH2 gene deleted mice ( IDH2 –/– ). Eight- to 10-week-old female IDH2 –/– mice and wild type ( IDH2 +/+ ) littermates were subjected to UUO and kidneys were harvested 5 days after UUO. IDH2 was not detected in the kidneys of IDH2 –/– mice, while UUO decreased IDH2 in IDH2 +/+ mice. UUO increased the expressions of markers of oxidative stress in both IDH2 +/+ and IDH2 –/– mice, and these changes were greater in IDH2 –/– mice compared to IDH2 +/+ mice. Bone marrow-derived macrophages of IDH2 –/– mice showed a more migrating phenotype with greater ruffle formation and Rac1 distribution than that of IDH2 +/+ mice. Correspondently, UUO-induced infiltration of monocytes/macrophages was greater in IDH2 –/– mice compared to IDH2 +/+ mice. Taken together, these data demonstrate that IDH2 plays a protective role against UUO-induced inflammation through inhibition of oxidative stress and macrophage infiltration.
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