Yuguo Chen

Inhibition of aldehyde dehydrogenase 2 by oxidative stress is associated with cardiac dysfunction in diabetic rats.

Left ventricular (LV) dysfunction is a common comorbidity in diabetic patients, although the molecular mechanisms underlying this cardiomyopathic feature are not completely understood. Aldehyde dehydrogenase 2 (ALDH2) has been considered a key cardioprotective enzyme susceptible to oxidative inactivation. We hypothesized that hyperglycemia-induced oxidative stress would influence ALDH2 activity, and ALDH2 inhibition would lead to cardiac functional alterations in diabetic rats. Diabetes was induced by intraperitoneal (i.p.) injection of 60 mg/kg streptozotocin. Rats were divided randomly into four groups: control, untreated diabetic, diabetic treated with N-acetylcysteine (NAC) and diabetic treated with a-lipoic acid (α-LA). Cardiac contractile function, oxidative stress markers and reactive oxygen species (ROS) levels were assessed. ALDH2 activity and expression also were determined. The role of ALDH2 activity in change in hyperglycemia-induced mitochondrial membrane potential (Δψ) was tested in cultured neonatal cardiomyocytes. Myocardial MDA content and ROS were significantly higher in diabetic rats than in controls, whereas GSH content and Mn-SOD activity were decreased in diabetic rats. Compared with controls, diabetic rats exhibited significant reduction in LV ejection fraction and fractional shortening, accompanied by decreases in ALDH2 activity and expression. NAC and α-LA attenuated these changes. Mitochondrial Δψ was decreased greatly with hyperglycemia treatment, and high glucose combined with ALDH2 inhibition with daidzin further decreased Δψ The ALDH2 activity can be regulated by oxidative stress in the diabetic rat heart. ALDH2 inhibition may be associated with LV reduced contractility, and mitochondrial impairment aggravated by ALDH2 inhibition might reflect an underlying mechanism which causes cardiac dysfunction in diabetic rats.

Acetylation-dependent regulation of mitochondrial ALDH2 activation by SIRT3 mediates acute ethanol-induced eNOS activation.

Moderate alcohol consumption has beneficial effects on endothelial nitric‐oxide synthase (eNOS) activation, which can engender an array of anti‐atherogenic actions. Here we show that in human aortic endothelial cells (HAECs), rapid activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) mediates ethanol‐induced eNOS activation by preventing reactive oxygen species (ROS) accumulation. Furthermore, activation of ALDH2 by ethanol is due to its hyperacetylation by SIRT3 inactivation. These data suggest that ethanol‐induced eNOS activation in HAECs may be dependent on ALDH2 hyperacetylation by SIRT3 inactivation.

Arginase I Attenuates Inflammatory Cytokine Secretion Induced by Lipopolysaccharide in Vascular Smooth Muscle Cells

Objective—Inflammation plays an important role in atherosclerosis. Arginase I (Arg I) promotes the proliferation of vascular smooth muscle cells; however, the effect of Arg I on inflammation remains unknown. The present study investigated the role of Arg I in inflammation in vitro and in vivo. Methods and Results—Quantitative reverse transcription–polymerase chain reaction and Western blot analysis demonstrated that Arg I inhibited tumor necrosis factor-&agr; production induced by lipopolysaccharide in human aortic smooth muscle cells. Inducible nitric oxide synthase substrate competition and nuclear factor-&kgr;B activation were main contributors to lipopolysaccharide-mediated inflammatory cytokine generation. However, Arg I could attenuate the function of inducible nitric oxide synthase and inhibit the subsequent nuclear factor-&kgr;B activation, leading to inhibition of tumor necrosis factor-&agr; generation. Furthermore, upregulation of Arg I significantly decreased macrophage infiltration and inflammation in atherosclerotic plaque of rabbits, whereas downregulation of Arg I aggravated these adverse effects. Conclusion—The results indicate the antiinflammatory effects of Arg I and suggest an unexpected beneficial role of Arg I in inflammatory disease.

Angiotensin II type 1 receptor gene A1166C polymorphism and essential hypertension in Chinese: a meta-analysis

Introduction. We performed a meta-analysis with the aim of assessing the association of the angiotensin II type 1 (AT1) receptor gene A1166C polymorphism with essential hypertension in Chinese case-control studies. Methods. Studies were searched from the Chinese Biomedicine Database, the China National Knowledge Infrastructure platform, Pubmed and Medline, using the search terms ‘hypertension’, ‘angiotensin II type 1 receptor’, ‘AT1R’, ‘polymorphism’, ‘China’ and ‘Chinese’, without limiting to any specific language. The strength of the association between the A1166C polymorphism and hypertension was evaluated by the odds ratio (OR) with the corresponding 95% confidence interval (CI). The analyses were performed with Cochrane RevMan software version 4.2. Results. Overall, the variant genotype AC/CC was associated with a statistically increased essential hypertension risk with the pooled OR 1.48 (95% CI: 1.20—1.83). In the subgroup analyses, the association was also significant among studies using Northern populations, Southern populations, Han Chinese and hospital-based controls. The age did not influence the relationship between the AT 1 receptor A1166C polymorphism and hypertension in the subgroup analyses. Conclusions. The present meta-analysis suggests that the AT1 receptor 1166 AC/CC genotype is associated with susceptibility to hypertension in the Chinese population.

Angiotensin-(1-7) Suppresses Hepatocellular Carcinoma Growth and Angiogenesis via Complex Interactions of Angiotensin II Type 1 Receptor, Angiotensin II Type 2 Receptor and Mas Receptor.

We recently confirmed that angiotensin II (Ang II) type 1 receptor (AT1R) was overexpressed in hepatocellular carcinoma tissue using a murine hepatoma model. Angiotensin(Ang)-(1-7) has been found beneficial in ameliorating lung cancer and prostate cancer. Which receptor of Ang-(1-7) is activated to mediate its effects is much speculated. This study was designed to investigate the effects of Ang-(1-7) on hepatocellular carcinoma, as well as the probable mechanisms. H22 hepatoma-bearing mice were randomly divided into five groups for treatment: mock group, low-dose Ang-(1-7), high-dose Ang-(1-7), high-dose Ang-(1-7) + A779 and high-dose Ang-(1-7) + PD123319. Ang-(1-7) treatment inhibited tumor growth time- and dose-dependently by arresting tumor proliferation and promoting tumor apoptosis as well as inhibiting tumor angiogenesis. The effects of Ang-(1-7) on tumor proliferation and apoptosis were reversed by coadministration with A779 or PD123319, whereas the effects on tumor angiogenesis were completely reversed by A779 but not by PD123319. Moreover, Ang-(1-7) downregulated AT1R mRNA, upregulated mRNA levels of Ang II type 2 receptor (AT2R) and Mas receptor (MasR) and p38-MAPK phosphorylation and suppressed H22 cell-endothelial cell communication. Thus, Ang-(1-7) administration suppresses hepatocellular carcinoma via complex interactions of AT1R, AT2R and MasR and may provide a novel and promising approach for the treatment of hepatocellular carcinoma.

Effects and mechanisms of PPARα activator fenofibrate on myocardial remodelling in hypertension

Although peroxisome proliferator‐activated receptor α (PPARα) is highly expressed in the heart, the effects of PPARα on cardiac remodelling and the underlying mechanisms are unclear. The present study was undertaken to test the hypothesis that PPARα activator fenofibrate plays a key role in left ventricular hypertrophic remodelling via the formation of c‐fos/c‐jun heterodimers in spontaneous hypertensive rats (SHRs). Twenty‐four male 8‐week‐old SHRs were randomly divided into two groups, one group treated with oral saline (n= 10) and another treated with oral fenofibrate (60 mg.kg−1.d−1, n= 14). Ten same‐aged Wistar–Kyoto (WKY) rats were selected as a normal control group. Using echocardiography, immunohistochemistry, co‐immunoprecipitation, Western blot analysis and real‐time RT‐PCR, we showed that the left ventricular wall thickness and significantly reduced and left ventricular diastolic function improved in SHRs treated with fenofibrate compared with SHRs treated with saline. Similarly, the excessive collagen deposition and the up‐regulation of collagen I, collagen III, c‐fos and c‐jun seen in SHRs receiving saline were significantly attenuated in SHRs receiving fenofibrate. In addition, fenofibrate markedly decreased the expression of AP‐1 and c‐fos/c‐jun heterodimers (P < 0.01). These results demonstrated that PPARα activator fenofibrate may exert a protective effect on cardiac remodelling in SHRs by decreasing the expression of c‐fos and c‐jun and suppressing the formation of c‐fos/c‐jun heterodimers, which may further inhibit transcription of the downstream genes involved in the pathogenesis of left ventricular hypertrophy induced by hypertension.

Aldehyde Dehydrogenase 2 Has Cardioprotective Effects on Myocardial Ischaemia/Reperfusion Injury via Suppressing Mitophagy

Mitophagy, a selective form of autophagy, is excessively activated in myocardial ischemia/reperfusion (I/R). The study investigated whether aldehyde dehydrogenase 2 (ALDH2) exerted its cardioprotective effect by regulating mitophagy. Myocardial infarct size and apoptosis after I/R in rats were ameliorated by Alda-1, an ALDH2 activator, and aggravated by ALDH2 inhibition. Both in I/R rats and hypoxia/reoxygenation H9C2 cells, ALDH2 activation suppressed phosphatase and tensin homolog-induced putative kinase 1 (PINK1)/Parkin expression, regulating mitophagy, by preventing 4-hydroxynonenal, reactive oxygen species and mitochondrial superoxide accumulation. Furthermore, the effect was enhanced by ALDH2 inhibition. Thus, ALDH2 may protect hearts against I/R injury by suppressing PINK1/Parkin–dependent mitophagy.

Effects of ulinastatin, a urinary trypsin inhibitor, on synaptic plasticity and spatial memory in a rat model of cerebral ischemia/reperfusion injury.

Established therapies for cerebral ischemia-reperfusion injury are currently limited. The urinary trypsin inhibitor ulinastatin (UTI) is considered cytoprotective against ischemia-reperfusion injury in internal organs through its anti-inflammatory activity. We aimed to investigate the neuroprotective effects of UTI on learning and memory of rats after cerebral ischemia-reperfusion injury. Rats were treated with UTI at 10,000 U/kg body weight, then underwent ischemia and reperfusion by the middle cerebral arterial occlusion (MCAO) method. At various times after the onset of reperfusion, we evaluated neurologic impairment scores. Brain sections underwent immunohistochemical staining for synaptophysin and calcium-binding protein S100β. Other rats underwent the Morris water maze test to determine the effects of UTI on learning and memory. Spatial reference learning and memory were improved with UTI treatment by down-regulating S100β-positive cells and preventing the loss of neural cells. Thus, UTI has a neuroprotective role on synaptic plasticity and spatial memory with cerebral ischemia-reperfusion injury in rats.

The role of thrombospondin-1-mediated TGF-β1 on collagen type III synthesis induced by high glucose

Transforming growth factor-β1 (TGF-β1) has been thought to play a major role during cardiac fibrosis in the development of diabetic cardiomyopathy, and cardiac fibrosis mainly as a result of an increase of collagen type III occurs in the human hearts with diabetes. Thrombospondin-1 (TSP-1) has been reported to activate the latent complex of TGF-β1. We examined the effects of TSP-1 on the expression of TGF-β1 and collagen type III by rat cardiac fibroblasts in high ambient glucose. We demonstrated that high glucose induces the mRNA and protein expression of collagen type III, TGF-β1, and TSP-1. Furthermore, the mRNA and protein expression of collagen type III induced by high glucose was downregulated after treatment with TGF-β1 antibody, or TSP-1 siRNA. The expression of TGF-β1 increased by high glucose was also reversed after treatment with TSP-1 siRNA. Our findings suggest that the TSP-1 participates in the upregulation of TGF-β1, collagen type III by high glucose and may provide new therapeutic strategies for diabetic cardiomyopathy.

Activin receptor-like kinase 7 mediates high glucose-induced H9c2 cardiomyoblast apoptosis through activation of Smad2/3

Cardiomyocyte apoptosis is an important pathological change of diabetic cardiomyopathy. How the elevated glucose levels cause cell apoptosis remains unknown. The aim of our study was to investigate whether activin receptor-like kinase 7 (ALK7)-Smad2/3 signaling pathway plays an important role in high glucose-induced cardiomyocyte apoptosis. H9c2 cardiomyoblasts and neonatal rat cardiomyocytes were treated with 33mmol/l glucose. The expression of ALK7, Smad2 and Smad3 were inhibited by small interfering RNA respectively. The level of ALK7, total Smad2/3, phosphorylated Smad2/3, B-cell lymphoma-2 (Bcl-2) and cleaved Caspase3 were evaluated using western blot. The apoptosis rate was detected by flow cytometer. High glucose treatment caused the apoptosis of H9c2 cardiomyocyte and the inhibition of Smad2 or Smad3 attenuated this apoptosis. ALK7 existed in both H9c2 cardiomyoblasts and neonatal rat cardiomyocytes and high ambient glucose upregulated its expression. The increased expression level of cleaved Caspase3 and apoptosis rate and decreased expression of Bcl-2 were reversed after ALK7 was inhibited. The expression of phosphorylated Smad2/3 also decreased after the knockdown of ALK7. Our findings suggest that ALK7 mediates high ambient glucose-induced H9c2 cardiomyoblasts apoptosis through the activation of Smad2/3.