title: Role of resistin in cardiac contractility and hypertrophy.
abstract: Cardiovascular sequelae including diabetic cardiomyopathy constitute the major cause of death in diabetic patients. Although several factors may contribute to the development of this cardiomyopathy, the underlying molecular/cellular mechanisms leading to cardiac dysfunction are still partially understood. Recently, a novel paradigm for the role of the adipocytokine resistin in diabetes has emerged. Resistin has been proposed to be a link between obesity, insulin resistance and diabetes. Using microarray analysis, we have recently found that cardiomyocytes isolated from type 2 diabetic hearts express high levels of resistin. However, the function of resistin with respect to cardiac function is unknown. In this study we show that resistin is not only expressed in the heart, but also promotes cardiac hypertrophy. Adenovirus-mediated overexpression of resistin in cultured neonatal rat ventricular myocytes (NRVM) significantly increased sarcomere organization and cell size, increased protein synthesis and increased the expression of atrial natriuretic factor and beta-myosin heavy chain. Overexpression of resistin in NRVM was also associated with activation of the mitogen-activated protein (MAP) kinases, ERK1/2 and p38, as well as increased Ser-636 phosphorylation of insulin receptor substrate-1 (IRS-1), indicating that IRS-1/MAPK pathway may be involved in the observed hypertrophic response. Overexpression of resistin in adult cultured cardiomyocytes significantly altered myocyte mechanics by depressing cell contractility as well as contraction and relaxation velocities. Intracellular Ca(2+) measurements showed slower Ca(2+) transients decay in resistin-transduced myocytes compared to controls, suggesting impaired cytoplasmic Ca(2+) clearing or alterations in myofilament activation. We conclude that resistin overexpression alters cardiac contractility, confers to primary cardiomyocytes all the features of the hypertrophic phenotype and promotes cardiac hypertrophy possibly via the IRS-1/MAPK pathway.
authors.affiliation: Cardiovascular Research Center, Mount Sinai School of Medicine, USA.
authors.forename: Maengjo
authors.initials: M
authors.lastname: Kim
authors.forename: Jae Kyun
authors.initials: JK
authors.lastname: Oh
authors.forename: Susumu
authors.initials: S
authors.lastname: Sakata
authors.forename: Iifan
authors.initials: I
authors.lastname: Liang
authors.forename: Woojin
authors.initials: W
authors.lastname: Park
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: Djamel
authors.initials: D
authors.lastname: Lebeche
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D010641:Phenotype; D051381:Rats; D020334:Rats, Inbred OLETF; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D052243:Resistin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
chemical_list: D052243:Resistin; C499622:Retn protein, rat; D020928:Mitogen-Activated Protein Kinases