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Article: Inhibition of PKCβ2 overexpression ameliorates myocardial ischaemia/reperfusion injury in diabetic rats via restoring caveolin-3/Akt signaling

TitleInhibition of PKCβ2 overexpression ameliorates myocardial ischaemia/reperfusion injury in diabetic rats via restoring caveolin-3/Akt signaling
Authors
KeywordsCaveolin-3
Protein kinase Cβ
Myocardial ischaemia/reperfusion injury
Diabetes
Issue Date2015
Citation
Clinical Science, 2015, v. 129, n. 4, p. 331-344 How to Cite?
Abstract© 2015 The Author(s).Activation of PKCβ (protein kinase Cβ) plays a critical role in myocardial I/R (ischaemia/reperfusion) injury in non-diabetic rodents. In the myocardium of diabetes, PKCβ2 overexpression is associated with increased vulnerability to post-ischaemic I/R injury with concomitantly impaired cardiomyocyte Cav (caveolin)-3 and Akt signalling compared with non-diabetic rats. We hypothesized that myocardial PKCβ overexpression in diabetes exacerbates myocardial I/R injury through impairing Cav-3/Akt signalling. Streptozotocin-induced diabetic rats were treated with the selective PKCβ inhibitor ruboxistaurin (RBX, 1 mg/kg per day) for 4 weeks, starting from 1 week after diabetes induction, before inducing myocardial I/R achieved by occluding the left descending coronary artery followed by reperfusion. Cardiac function was measured using a pressure-volume conductance system. In an in vitro study, cardiac H9C2 cells were exposed to high glucose (30 mmol/l) and subjected to hypoxia followed by reoxygenation (H/R) in the presence or absence of the selective PKCβ2 inhibitor CGP53353 (1 μmol/l), siRNAs of PKCβ2 or Cav-3 or Akt. Cell apoptosis and mitochondrial membrane potential were assessed by TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling) and JC-1 staining respectively. RBX significantly decreased post-ischaemic myocardial infarct size (35± 5% compared with 49± 3% in control, P < 0.05) and attenuated cardiac dysfunction, and prevented the reduction in cardiac Cav-3 and enhanced phosphorylated/activated Akt (p-Akt) in diabetic rats (P < 0.05). H/R increased cardiomyocyte injury under high glucose conditions as was evident by increased TUNEL-positive and increased JC-1 monomeric cells (P < 0.05 compared with control), accompanied with increased PKCβ2 phosphorylation/activation and decreased Cav-3 expression. Either CGP53353 or PKCβ2 siRNA significantly attenuated all of these changes and enhanced p-Akt. Cav-3 gene knockdown significantly reduced p-Akt and increased post-hypoxic cellular and mitochondrial injury despite a concomitant reduction in PKCβ2 phosphorylation. PKCβ2 inhibition with RBX protects diabetic hearts from myocardial I/R injury through Cav-3-dependent activation of Akt.
Persistent Identifierhttp://hdl.handle.net/10722/237985
ISSN
2023 Impact Factor: 6.7
2023 SCImago Journal Rankings: 1.565
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLiu, Yanan-
dc.contributor.authorJin, Jiqin-
dc.contributor.authorQiao, Shigang-
dc.contributor.authorLei, Shaoqing-
dc.contributor.authorLiao, Songyan-
dc.contributor.authorGe, Zhi Dong-
dc.contributor.authorLi, Haobo-
dc.contributor.authorWong, Gordon Tin chun-
dc.contributor.authorIrwin, Michael G.-
dc.contributor.authorXia, Zhengyuan-
dc.date.accessioned2017-02-03T02:12:32Z-
dc.date.available2017-02-03T02:12:32Z-
dc.date.issued2015-
dc.identifier.citationClinical Science, 2015, v. 129, n. 4, p. 331-344-
dc.identifier.issn0143-5221-
dc.identifier.urihttp://hdl.handle.net/10722/237985-
dc.description.abstract© 2015 The Author(s).Activation of PKCβ (protein kinase Cβ) plays a critical role in myocardial I/R (ischaemia/reperfusion) injury in non-diabetic rodents. In the myocardium of diabetes, PKCβ2 overexpression is associated with increased vulnerability to post-ischaemic I/R injury with concomitantly impaired cardiomyocyte Cav (caveolin)-3 and Akt signalling compared with non-diabetic rats. We hypothesized that myocardial PKCβ overexpression in diabetes exacerbates myocardial I/R injury through impairing Cav-3/Akt signalling. Streptozotocin-induced diabetic rats were treated with the selective PKCβ inhibitor ruboxistaurin (RBX, 1 mg/kg per day) for 4 weeks, starting from 1 week after diabetes induction, before inducing myocardial I/R achieved by occluding the left descending coronary artery followed by reperfusion. Cardiac function was measured using a pressure-volume conductance system. In an in vitro study, cardiac H9C2 cells were exposed to high glucose (30 mmol/l) and subjected to hypoxia followed by reoxygenation (H/R) in the presence or absence of the selective PKCβ2 inhibitor CGP53353 (1 μmol/l), siRNAs of PKCβ2 or Cav-3 or Akt. Cell apoptosis and mitochondrial membrane potential were assessed by TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling) and JC-1 staining respectively. RBX significantly decreased post-ischaemic myocardial infarct size (35± 5% compared with 49± 3% in control, P < 0.05) and attenuated cardiac dysfunction, and prevented the reduction in cardiac Cav-3 and enhanced phosphorylated/activated Akt (p-Akt) in diabetic rats (P < 0.05). H/R increased cardiomyocyte injury under high glucose conditions as was evident by increased TUNEL-positive and increased JC-1 monomeric cells (P < 0.05 compared with control), accompanied with increased PKCβ2 phosphorylation/activation and decreased Cav-3 expression. Either CGP53353 or PKCβ2 siRNA significantly attenuated all of these changes and enhanced p-Akt. Cav-3 gene knockdown significantly reduced p-Akt and increased post-hypoxic cellular and mitochondrial injury despite a concomitant reduction in PKCβ2 phosphorylation. PKCβ2 inhibition with RBX protects diabetic hearts from myocardial I/R injury through Cav-3-dependent activation of Akt.-
dc.languageeng-
dc.relation.ispartofClinical Science-
dc.subjectCaveolin-3-
dc.subjectProtein kinase Cβ-
dc.subjectMyocardial ischaemia/reperfusion injury-
dc.subjectDiabetes-
dc.titleInhibition of PKCβ2 overexpression ameliorates myocardial ischaemia/reperfusion injury in diabetic rats via restoring caveolin-3/Akt signaling-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1042/CS20140789-
dc.identifier.pmid25849791-
dc.identifier.scopuseid_2-s2.0-84938513239-
dc.identifier.hkuros249414-
dc.identifier.hkuros261677-
dc.identifier.volume129-
dc.identifier.issue4-
dc.identifier.spage331-
dc.identifier.epage344-
dc.identifier.isiWOS:000361010300004-
dc.identifier.issnl0143-5221-

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