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N-acetylcysteine attenuates myocardial dysfunction and postischemic injury by restoring caveolin-3/eNOS signaling in diabetic rats.
Cardiovasc Diabetol. 2016 10 12; 15(1):146.CD

Abstract

BACKGROUND

Patients with diabetes are prone to develop cardiac hypertrophy and more susceptible to myocardial ischemia-reperfusion (I/R) injury, which are concomitant with hyperglycemia-induced oxidative stress and impaired endothelial nitric oxide (NO) synthase (eNOS)/NO signaling. Caveolae are critical in the transduction of eNOS/NO signaling in cardiovascular system. Caveolin (Cav)-3, the cardiomyocytes-specific caveolae structural protein, is decreased in the diabetic heart in which production of reactive oxygen species are increased. We hypothesized that treatment with antioxidant N-acetylcysteine (NAC) could enhance cardiac Cav-3 expression and attenuate caveolae dysfunction and the accompanying eNOS/NO signaling abnormalities in diabetes.

METHODS

Control or streptozotocin-induced diabetic rats were either untreated or treated with NAC (1.5 g/kg/day, NAC) by oral gavage for 4 weeks. Rats in subgroup were randomly assigned to receive 30 min of left anterior descending artery ligation followed by 2 h of reperfusion. Isolated rat cardiomyocytes or H9C2 cells were exposed to low glucose (LG, 5.5 mmol/L) or high glucose (HG, 25 mmol/L) for 36 h before being subjected to 4 h of hypoxia followed by 4 h of reoxygenation (H/R).

RESULTS

NAC treatment ameliorated myocardial dysfunction and cardiac hypertrophy, and attenuated myocardial I/R injury and post-ischemic cardiac dysfunction in diabetic rats. NAC attenuated the reductions of NO, Cav-3 and phosphorylated eNOS and mitigated the augmentation of O2-, nitrotyrosine and 15-F2t-isoprostane in diabetic myocardium. Immunofluorescence analysis demonstrated the colocalization of Cav-3 and eNOS in isolated cardiomyocytes. Immunoprecipitation analysis revealed that diabetic conditions decreased the association of Cav-3 and eNOS in isolated cardiomyocytes, which was enhanced by treatment with NAC. Disruption of caveolae by methyl-β-cyclodextrin or Cav-3 siRNA transfection reduced eNOS phosphorylation. NAC treatment attenuated the reductions of Cav-3 expression and eNOS phosphorylation in HG-treated cardiomyocytes or H9C2 cells. NAC treatment attenuated HG and H/R induced cell injury, which was abolished during concomitant treatment with Cav-3 siRNA or eNOS siRNA.

CONCLUSIONS

Hyperglycemia-induced inhibition of eNOS activity might be consequences of caveolae dysfunction and reduced Cav-3 expression. Antioxidant NAC attenuated myocardial dysfunction and myocardial I/R injury by improving Cav-3/eNOS signaling.

Authors+Show Affiliations

Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.Department of Anesthesiology, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.Department of Anesthesiology, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.Department of Anesthesiology, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. zyxia@hku.hk. Department of Anesthesiology, The University of Hong Kong, Hong Kong SAR, China. zyxia@hku.hk.Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China. leishaoqing@163.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27733157

Citation

Su, Wating, et al. "N-acetylcysteine Attenuates Myocardial Dysfunction and Postischemic Injury By Restoring caveolin-3/eNOS Signaling in Diabetic Rats." Cardiovascular Diabetology, vol. 15, no. 1, 2016, p. 146.
Su W, Zhang Y, Zhang Q, et al. N-acetylcysteine attenuates myocardial dysfunction and postischemic injury by restoring caveolin-3/eNOS signaling in diabetic rats. Cardiovasc Diabetol. 2016;15(1):146.
Su, W., Zhang, Y., Zhang, Q., Xu, J., Zhan, L., Zhu, Q., Lian, Q., Liu, H., Xia, Z. Y., Xia, Z., & Lei, S. (2016). N-acetylcysteine attenuates myocardial dysfunction and postischemic injury by restoring caveolin-3/eNOS signaling in diabetic rats. Cardiovascular Diabetology, 15(1), 146.
Su W, et al. N-acetylcysteine Attenuates Myocardial Dysfunction and Postischemic Injury By Restoring caveolin-3/eNOS Signaling in Diabetic Rats. Cardiovasc Diabetol. 2016 10 12;15(1):146. PubMed PMID: 27733157.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - N-acetylcysteine attenuates myocardial dysfunction and postischemic injury by restoring caveolin-3/eNOS signaling in diabetic rats. AU - Su,Wating, AU - Zhang,Yuan, AU - Zhang,Qiongxia, AU - Xu,Jinjin, AU - Zhan,Liying, AU - Zhu,Qiqi, AU - Lian,Qingquan, AU - Liu,Huimin, AU - Xia,Zhong-Yuan, AU - Xia,Zhengyuan, AU - Lei,Shaoqing, Y1 - 2016/10/12/ PY - 2016/07/14/received PY - 2016/09/28/accepted PY - 2016/10/14/entrez PY - 2016/10/14/pubmed PY - 2017/2/14/medline KW - Caveolin-3 KW - Diabetes KW - Diabetic cardiomyopathy KW - Myocardial ischemia–reperfusion injury KW - N-acetylcysteine SP - 146 EP - 146 JF - Cardiovascular diabetology JO - Cardiovasc Diabetol VL - 15 IS - 1 N2 - BACKGROUND: Patients with diabetes are prone to develop cardiac hypertrophy and more susceptible to myocardial ischemia-reperfusion (I/R) injury, which are concomitant with hyperglycemia-induced oxidative stress and impaired endothelial nitric oxide (NO) synthase (eNOS)/NO signaling. Caveolae are critical in the transduction of eNOS/NO signaling in cardiovascular system. Caveolin (Cav)-3, the cardiomyocytes-specific caveolae structural protein, is decreased in the diabetic heart in which production of reactive oxygen species are increased. We hypothesized that treatment with antioxidant N-acetylcysteine (NAC) could enhance cardiac Cav-3 expression and attenuate caveolae dysfunction and the accompanying eNOS/NO signaling abnormalities in diabetes. METHODS: Control or streptozotocin-induced diabetic rats were either untreated or treated with NAC (1.5 g/kg/day, NAC) by oral gavage for 4 weeks. Rats in subgroup were randomly assigned to receive 30 min of left anterior descending artery ligation followed by 2 h of reperfusion. Isolated rat cardiomyocytes or H9C2 cells were exposed to low glucose (LG, 5.5 mmol/L) or high glucose (HG, 25 mmol/L) for 36 h before being subjected to 4 h of hypoxia followed by 4 h of reoxygenation (H/R). RESULTS: NAC treatment ameliorated myocardial dysfunction and cardiac hypertrophy, and attenuated myocardial I/R injury and post-ischemic cardiac dysfunction in diabetic rats. NAC attenuated the reductions of NO, Cav-3 and phosphorylated eNOS and mitigated the augmentation of O2-, nitrotyrosine and 15-F2t-isoprostane in diabetic myocardium. Immunofluorescence analysis demonstrated the colocalization of Cav-3 and eNOS in isolated cardiomyocytes. Immunoprecipitation analysis revealed that diabetic conditions decreased the association of Cav-3 and eNOS in isolated cardiomyocytes, which was enhanced by treatment with NAC. Disruption of caveolae by methyl-β-cyclodextrin or Cav-3 siRNA transfection reduced eNOS phosphorylation. NAC treatment attenuated the reductions of Cav-3 expression and eNOS phosphorylation in HG-treated cardiomyocytes or H9C2 cells. NAC treatment attenuated HG and H/R induced cell injury, which was abolished during concomitant treatment with Cav-3 siRNA or eNOS siRNA. CONCLUSIONS: Hyperglycemia-induced inhibition of eNOS activity might be consequences of caveolae dysfunction and reduced Cav-3 expression. Antioxidant NAC attenuated myocardial dysfunction and myocardial I/R injury by improving Cav-3/eNOS signaling. SN - 1475-2840 UR - https://www.unboundmedicine.com/medline/citation/27733157/N_acetylcysteine_attenuates_myocardial_dysfunction_and_postischemic_injury_by_restoring_caveolin_3/eNOS_signaling_in_diabetic_rats_ L2 - https://cardiab.biomedcentral.com/articles/10.1186/s12933-016-0460-z DB - PRIME DP - Unbound Medicine ER -