Aldehyde dehydrogenase 2 Glu504Lys variant predicts a worse prognosis of acute coronary syndrome patients.

Aldehyde dehydrogenase 2 (ALDH2) Glu504Lys variant was an independent risk factor for acute coronary syndrome (ACS). However, there are lacking researches about the relationship between the variant and prognosis of ACS. In the prospective study, 377 ACS patients were grouped into the wild-type (*1/*1) and the mutation (*2/*2 + *1/*2) groups according to genotype detection. Compared with the wild-type group, incidences of major adverse cardiac events (MACE) and cardiac death were both higher in the mutation group (9.2% vs 21.0%, P = .002; 5.2% vs 12.2%, P = .026); the MACE-free and the cardiac-death-free cumulative survival rates were obviously lower in the mutation group. Moreover, the mutant genotypes were associated with significantly increased risk of MACE and cardiac death (HR 2.443, 95%CI: 1.390-4.296, P = .002; HR 2.727, 95%CI: 1.303-5.708, P = .008). These results suggested that ALDH2 Glu504Lys variant could predict a worse prognosis of ACS patients.

Poly(ADP-ribose) polymerase 1 deficiency increases nitric oxide production and attenuates aortic atherogenesis through downregulation of arginase II.

Poly (ADP-ribose) polymerase (PARP) plays an important role in endothelial dysfunction, leading to atherogenesis and vascular-related diseases. However, whether PARP regulates nitric oxide (NO), a key regulator of endothelial function, is unclear so far. We investigated whether inhibition of PARP-1, the most abundant PARP isoform, prevents atherogenesis by regulating NO production and tried to elucidate the possible mechanisms involved in this phenomenon. In apolipoprotein E-deficient (apoE-/- ) mice fed a high-cholesterol diet for 12 weeks, PARP-1 inhibition via treatment with 3,4-dihydro-54-(1-piperindinyl) butoxy-1(2H)-isoquinoline (DPQ) or PARP-1 gene knockout reduced aortic atherosclerotic plaque areas (49% and 46%, respectively). Both the groups showed restored NO production in mouse aortas with reduced arginase II (Arg II) expression compared to that in the controls. In mouse peritoneal macrophages and aortic endothelial cells (MAECs), PARP-1 knockout resulted in lowered Arg II expression. Moreover, phosphorylation of endothelial NO synthase (eNOS) was preserved in the aortas and MAECs when PARP-1 was inhibited. Reduced NO production in vitro due to PARP-1 deficiency could be restored by treating the MAECs with oxidized low-density lipoprotein treatment, but this effect could not be achieved with peritoneal macrophages, which was likely due to a reduction in the expression of induced NOS expression. Our findings indicate that PARP-1 inhibition may attenuate atherogenesis by restoring NO production in endothelial cells and thus by reducing Arg II expression and consequently arginase the activity.

Poly(ADP-ribose) polymerase 1 inhibition protects against low shear stress induced inflammation.

BACKGROUND: Atherosclerosis begins as local inflammation of vessels at sites of disturbed flow, where low shear stress (LSS) leads to mechanical irritation and plaque development and progression. Nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP-1) is associated with the inflammation response during atherosclerosis. We investigated the role and underlying mechanism of PARP-1 in LSS-induced inflammation in human umbilical vein endothelial cells (HUVECs). METHODS AND RESULTS: HUVECs were simulated by LSS (0.4Pa). PARP-1 expression was inhibited by ABT888 or siRNA. The inducible nitric oxide synthase (iNOS) and intercellular adhesion molecular-1 (ICAM-1) expression was regulated by LSS in a time dependent manner. LSS could increase superoxide production and 3-nitrotyrosine formation. LSS induced DNA damage as assessed by H2A.X phosphorylation and comet assay. Compared with cells under static, LSS increased PARP-1 expression and PAR formation via MEK/ERK signaling pathway. PARP-1 inhibition increased Sirt1 activity through an increased intracellular nicotinamide adenine dinucleotide (NAD(+)) level. Moreover, PARP-1 inhibition attenuated LSS-induced iNOS and ICAM-1 upregulation by inhibiting nuclear factor kappa B (NF-κB) nuclear translocation and activity, with a reduced NF-κB phosphorylation. CONCLUSIONS: LSS induced oxidative damage and PARP-1 activation via MEK/ERK pathway. PARP-1 inhibition restored Sirt1 activity by increasing NAD(+) level and decreased iNOS and ICAM-1 expression by inhibiting NF-κB nuclear translocation and activity as well as NF-κB phosphorylation. PARP-1 played a fundamental role in LSS induced inflammation. Inhibition of PARP-1 might be a mechanism for treatment of inflammation response during atherosclerosis.

Poly(ADP-ribose) polymerase inhibition prevents reactive oxygen species induced inhibition of aldehyde dehydrogenase2 activity.

Lipid peroxidation plays a critical role in cardiovascular diseases. Aldehydes are the major end products of lipid peroxidation and can be metabolized into less reactive chemical species by aldehyde dehydrogenase 2 (ALDH2). However, ALDH2 dehydrogenase activity can be affected by many factors including reactive oxygen species. To elucidate how reactive oxygen species inhibit ALDH2 dehydrogenase activity, we stimulated human aortic endothelial cells (HAECs) with oxidized low-density lipoproteins (ox-LDL) and performed a myocardial ischemia-reperfusion model. Ox-LDL treatment and ischemia-reperfusion injury inhibited ALDH2 dehydrogenase activity. Poly(ADP-ribose) polymerase (PARP) was activated by ox-LDL stimulation and ischemia-reperfusion injury and PARP inhibition partly restored ALDH2 dehydrogenase activity in ox-LDL treated HAECs and ischemia-reperfusion rat hearts. SIRT3 was upregulated by ox-LDL stimulation and ischemia-reperfusion injury and downregulated by PARP inhibition. Using siRNA to knock down SIRT3, we demonstrated that SIRT3 mediated deacetylation decreased ALDH2 dehydrogenase activity and PARP inhibition partly restored ALDH2 dehydrogenase activity through preventing SIRT3 expression and subsequently preserving ALDH2 acetylation.

Hyperglycemia induces apoptosis of pancreatic islet endothelial cells via reactive nitrogen species-mediated Jun N-terminal kinase activation.

Hyperglycemia significantly stimulates pancreatic islet endothelial cell apoptosis; however, the precise mechanisms are not fully understood. In the present study, treating pancreatic islet endothelial (MS-1) cells with high glucose (30mmol/l) but not mannitol significantly increased the number of apoptotic cells as compared with a physiological glucose concentration (5.5mmol/l). Hyperglycemia significantly stimulated the expression of inducible nitric oxide synthase (iNOS) and production of NO and peroxynitrite (ONOO(-)), relevant to MS-1 cell apoptosis. Moreover, induced reactive nitrogen species (RNS) significantly increased the expression of bax, cleaved caspase-3 and poly adenosine diphosphate (ADP)-ribose polymerase (PARP) via JNK activation, but the expression of bcl-2 was not altered. Furthermore, SP600125 (a specific inhibitor of JNK) and 1400W (a specific inhibitor of iNOS) significantly attenuated cell apoptosis induced by high glucose. Therefore, hyperglycemia triggers MS-1 cell apoptosis by activating an intrinsic-dependent apoptotic pathway via RNS-mediated JNK activation.

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-α production induced by lipopolysaccharide in human aortic smooth muscle cells. Inducible nitric oxide synthase substrate competition and nuclear factor-κB 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-κB activation, leading to inhibition of tumor necrosis factor-α 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. CONCLUSIONS: The results indicate the antiinflammatory effects of Arg I and suggest an unexpected beneficial role of Arg I in inflammatory disease.

Inhibition of c-Jun N-terminal kinase attenuates low shear stress-induced atherogenesis in apolipoprotein E-deficient mice.

Atherosclerosis begins as local inflammation of arterial walls at sites of disturbed flow, such as vessel curvatures and bifurcations with low shear stress. c-Jun NH2-terminal kinase (JNK) is a major regulator of flow-dependent gene expression in endothelial cells in atherosclerosis. However, little is known about the in vivo role of JNK in low shear stress in atherosclerosis. We aimed to observe the effect of JNK on low shear stress-induced atherogenesis in apolipoprotein E-deficient (ApoE(-/-)) mice and investigate the potential mechanism in human umbilical vein endothelial cells (HUVECs). We divided 84 male ApoE(-/-) mice into two groups for treatment with normal saline (NS) (n = 42) and JNK inhibitor SP600125 (JNK-I) (n = 42). Perivascular shear stress modifiers were placed around the right carotid arteries, and plaque formation was studied at low shear stress regions. The left carotid arteries without modifiers represented undisturbed shear stress as a control. The NS group showed atherosclerotic lesions in arterial regions with low shear stress, whereas the JNK-I group showed almost no atherosclerotic lesions. Corresponding to the expression of proatherogenic vascular cell adhesion molecule 1 (VCAM-1), phospho-JNK (p-JNK) level was higher in low shear stress regions with NS than with JNK-I inhibitor. In HUVECs under low shear stress, siRNA knockdown and SP600125 inhibition of JNK attenuated nuclear factor (NF)-κB activity and VCAM-1 expression. Furthermore, siRNA knockdown of platelet endothelial cell adhesion molecule 1 (PECAM-1) (CD31) reduced p-JNK and VCAM-1 levels after low shear stress stimulation. JNK may play a critical role in low shear stress-induced atherogenesis by a PECAM-1-dependent mechanosensory pathway and modulating NF-κB activity and VCAM-1 expression.

Intracoronary administration of nicorandil-induced cardiac arrest during primary percutaneous coronary intervention: A case report.

RATIONALE: Primary percutaneous coronary intervention (PPCI) is the most effective therapy for patients with an acute ST-segment elevation myocardial infarction (STEMI). However, up to half of STEMI patients suffer from coronary microvascular dysfunction, presenting as the slow flow or no-reflow phenomenon. PATIENTS CONCERNS: A 78-year-old man was admitted to the chest pain center with sudden chest pain and tightness for about an hour. DIAGNOSES: Electrocardiography demonstrated ST-segment elevation in leads II, III, aVF, and third-degree atrioventricular block. Coronary angiography showed acute total occlusion in the distal right coronary artery (RCA). INTERVENTIONS: PPCI was performed on the patient. After thrombus aspiration, a stent was placed in the distal RCA. As coronary angiography showed TIMI grade 2 flow in RCA, 6 mg nicorandil was intracoronary administrated in twice. Immediately, cardiac arrest occurred and cardiopulmonary resuscitation (CPR) was performed. OUTCOMES: The patient survived and had a good outcome during follow-up for >6 months. LESSONS: Up to now, there has been no case report of cardiac arrest caused by nicorandil. Although intracoronary nicorandil is one of the most commonly used methods to improve coronary flow, much more attention should be paid to side effects of nicorandil.

Aldehyde dehydrogenase 2 inhibits inflammatory response and regulates atherosclerotic plaque.

Previous studies demonstrated that aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism, which eliminates ALDH2 activity down to 1%-6%, is a susceptibility gene for coronary disease. Here we investigated the underlying mechanisms based on our prior clinical and experimental studies. Male apoE-/- mice were transfected with GFP, ALDH2-overexpression and ALDH2-RNAi lentivirus respectively (n=20 each) after constrictive collars were placed around the right common carotid arteries. Consequently, ALDH2 gene silencing led to an increased en face plaque area, more unstable plaque with heavier accumulation of lipids, more macrophages, less smooth muscle cells and collagen, which were associated with aggravated inflammation. However, ALDH2 overexpression displayed opposing effects. We also found that ALDH2 activity decreased in atherosclerotic plaques of human and aged apoE-/- mice. Moreover, in vitro experiments with human umbilical vein endothelial cells further illustrated that, inhibition of ALDH2 activity resulted in elevating inflammatory molecules, an increase of nuclear translocation of NF-κB, and enhanced phosphorylation of NF-κB p65, AP-1 c-Jun, Jun-N terminal kinase and p38 MAPK, while ALDH2 activation could trigger contrary effects. These findings suggested that ALDH2 can influence plaque development and vulnerability, and inflammation via MAPK, NF-κB and AP-1 signaling pathways.

Glucagon-like peptide 1 protects microvascular endothelial cells by inactivating the PARP-1/iNOS/NO pathway.

Increasing studies suggest that the activity of GLP-1 might be of significant importance in the development of type 2 diabetes beyond its serum glucose-lowering effects. However, to date, the anti-apoptosis mechanism by which GLP-1 acts on MILE SVEN 1 (MS-1) cells has not been fully explored with regard to the intracellular signaling pathway. Increasing evidence shows that apoptosis of islet microvascular endothelial cells (IMECs) participates in the pathogenesis of diabetes. We wondered whether GLP-1 exerts its anti-apoptosis effects by inactivating the PARP-1/iNOS/NO pathway in oxidized low-density-lipoprotein (oxLDL)-induced apoptosis in mouse IMECs (MS-1 cells), which may linked to GLP-1R/cAMP levels. MTT assay revealed that 2-h pre-incubation with GLP-1 markedly restored the oxLDL-induced loss of MS-1 viability in a concentration-dependent manner. This effect was accompanied by a significant decrease in intracellular nitric oxide (NO) activity. Moreover, GLP-1 suppressed lipid peroxidation, restored the activities of endogenous antioxidants, and decreased the level of NO. Pre-incubating MS-1 cells with GLP-1 reduced cell apoptosis. Finally, GLP-1 could efficiently prevent the upregulation of poly(ADP-ribose) polymerase-1/nitrotyrosine and inducible NO synthase protein. Simultaneously, the expression of GLP-1 receptor and the level of cAMP was consistent with the administration of GLP-1. Our findings suggest that GLP-1 can effectively protect MS-1 cells against oxLDL-induced apoptosis, which may be important in preventing the pathogenesis of diabetes mellitus.