title: Partial deletion of ROCK2 protects mice from high-fat diet-induced cardiac insulin resistance and contractile dysfunction.
abstract: Obesity is associated with cardiac insulin resistance and contractile dysfunction, which contribute to the development of heart failure. The RhoA-Rho kinase (ROCK) pathway has been reported to modulate insulin resistance, but whether it is implicated in obesity-induced cardiac dysfunction is not known. To test this, wild-type (WT) and ROCK2(+/-) mice were fed normal chow or a high-fat diet (HFD) for 17 wk. Whole body insulin resistance, determined by an insulin tolerance test, was observed in HFD-WT, but not HFD-ROCK2(+/-), mice. The echocardiographically determined myocardial performance index, a measure of global systolic and diastolic function, was significantly increased in HFD-WT mice, indicating a deterioration of cardiac function. However, no change in myocardial performance index was found in hearts from HFD-ROCK2(+/-) mice. Speckle-tracking-based strain echocardiography also revealed regional impairment in left ventricular wall motion in hearts from HFD-WT, but not HFD-ROCK2(+/-), mice. Activity of ROCK1 and ROCK2 was significantly increased in hearts from HFD-WT mice, and GLUT4 expression was significantly reduced. Insulin-induced phosphorylation of insulin receptor substrate (IRS) Tyr(612), Akt, and AS160 was also impaired in these hearts, while Ser(307) phosphorylation of IRS was increased. In contrast, the increase in ROCK2, but not ROCK1, activity was prevented in hearts from HFD-ROCK2(+/-) mice, and cardiac levels of TNFα were reduced. This was associated with normalization of IRS phosphorylation, downstream insulin signaling, and GLUT4 expression. These data suggest that increased activation of ROCK2 contributes to obesity-induced cardiac dysfunction and insulin resistance and that inhibition of ROCK2 may constitute a novel approach to treat this condition.
authors.affiliation: Molecular and Cellular Pharmacology Research Group, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia, Egypt; and.
authors.forename: Hesham
authors.initials: H
authors.lastname: Soliman
authors.affiliation: Molecular and Cellular Pharmacology Research Group, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada;
authors.forename: Vongai
authors.initials: V
authors.lastname: Nyamandi
authors.affiliation: Molecular and Cellular Pharmacology Research Group, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada;
authors.forename: Marysol
authors.initials: M
authors.lastname: Garcia-Patino
authors.affiliation: Molecular and Cellular Pharmacology Research Group, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada;
authors.forename: Julia Nogueira
authors.initials: JN
authors.lastname: Varela
authors.affiliation: Molecular and Cellular Pharmacology Research Group, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada;
authors.forename: Girish
authors.initials: G
authors.lastname: Bankar
authors.affiliation: Molecular and Cellular Pharmacology Research Group, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada;
authors.forename: Guorong
authors.initials: G
authors.lastname: Lin
authors.affiliation: Neurosciences and Mental Health, Hospital for Sick Children, and Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Molecular and Cellular Pharmacology Research Group, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada; kmm@mail.ubc.ca.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: MacLeod
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D004452:Echocardiography; D020690:GTPase-Activating Proteins / Q000378:metabolism; D017353:Gene Deletion; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D051379:Mice; D009200:Myocardial Contraction / Q000235:genetics*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D054460:rho-Associated Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; D055504:Insulin Receptor Substrate Proteins; C495693:Slc2a4 protein, mouse; C505647:Tbc1d4 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; C515854:Rock1 protein, mouse; C515855:Rock2 protein, mouse; D054460:rho-Associated Kinases
keywords: ROCK2; heart; insulin receptor substrate phosphorylation; insulin signaling