title: SIRT2 regulates microtubule stabilization in diabetic cardiomyopathy.
abstract: Stable microtubules (MTs) is involved the mechanism of diabetic cardiomyopathy (DCM), which is induced by acetylation of α-tubulin. The present study investigated whether SIRT2, a deacetylase, regulates MT stability through α-tubulin deacetylation in DCM and whether the receptor of advanced glycation end products (AGEs) signaling pathway is involved in this effect. Type 1 diabetic mellitus (T1DM) rats model was established by a single intraperitoneal injection of streptozotocin (STZ, 65 mg/kg), and neonatal rat cardiomyocytes were also cultured. Heart function was detected by Doppler. MT stability was elevated by β-tubulin expression density. The protein expression of SIRT2, acetylated α-tubulin and AGEs receptor were detected by immunohistochemistry or Western blots. The interaction of SIRT2 and acetylated α-tubulin was detected by Co-immunoprecipitation. In an animal model of T1DM, Western blots and immunohistochemistry revealed downregulation of SIRT2 but upregulation of the acetylated α-tubulin protein. These effects were reduced by treatment of aminoguanidine, an inhibitor of AGEs production. HDAC6 expression did not regulated in heart. In primary cultures of neonatal rat cardiomyocytes, the AGEs treatment impaired the SIRT2/acetylated α-tubulin signaling pathway, and SIRT2-overexpression reversed the function of AGEs on cardiomyocytes. In addition, gene silencing of AGEs receptor alleviated the impairment effect of AGEs on cardiomyocytes. In conclusion, these data demonstrate that AGEs/AGEs receptor promote MT stabilization via the suppression of the SIRT2/acetylated α-tubulin signaling pathway in DCM development.
authors.affiliation: Department of Pharmacology, Medical College, Wuhan University of Science and Technology, Wuhan 430065, China; Brain and Cognitive Dysfunction Laboratory Medical College, Medical College,Wuhan University of Science and Technology, Wuhan 430065, China; Drug Research Base of Cardiovascular and Cerebral Vascular, Medical College, Wuhan University of Science and Technology, Wuhan 430065, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Department of Pharmacology, Medical College, Wuhan University of Science and Technology, Wuhan 430065, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhan
authors.affiliation: Department of Histology and Embryology, Medical College, Wuhan University of Science and Technology, Wuhan 430065, China.
authors.forename: Qian-Yi
authors.initials: QY
authors.lastname: Zhou
authors.affiliation: Department of Histology and Embryology, Medical College, Wuhan University of Science and Technology, Wuhan 430065, China.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Hunan University Of Chinese Medicine, Changsha 410208, China.
authors.forename: Xu-Meng
authors.initials: XM
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Medical College, Wuhan University of Science and Technology, Wuhan 430065, China; Brain and Cognitive Dysfunction Laboratory Medical College, Medical College,Wuhan University of Science and Technology, Wuhan 430065, China.
authors.forename: Xia-Min
authors.initials: XM
authors.lastname: Hu
authors.affiliation: Department of Histology and Embryology, Medical College, Wuhan University of Science and Technology, Wuhan 430065, China. Electronic address: y5307@126.com.
authors.forename: Xin-Chu
authors.initials: XC
authors.lastname: Yuan
mesh_terms: D000107:Acetylation; D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D058065:Diabetic Cardiomyopathies / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D015150:Echocardiography, Doppler; D015971:Gene Expression Regulation, Enzymologic; D017127:Glycation End Products, Advanced / Q000378:metabolism; D008297:Male; D008870:Microtubules / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000201:enzymology*; D011485:Protein Binding; D055550:Protein Stability; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D056565:Sirtuin 2 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014404:Tubulin / Q000378:metabolism; D016277:Ventricular Function, Left; D017725:Ventricular Pressure
chemical_list: C000593874:Ager protein, rat; D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; C097475:Sirt2 protein, rat; D014404:Tubulin; D056565:Sirtuin 2
keywords: Acetylated α-tubulin; Advanced glycation end products; Aminoguanidine; Diabetic cardiomyopathy; Receptor for advanced glycation end products; SIRT2