Signaling Mechanisms Induced by Mechanical Overload: Role in Myocardial Hypertrophy and Remodeling

• Grant number: 01/11698-1
• Support Opportunities: Research Projects - Thematic Grants
• Start date: January 01, 2003
• End date: December 31, 2006
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Kleber Gomes Franchini
• Grantee: Kleber Gomes Franchini
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• City of the host institution: Campinas

Abstract

Heart diseases are frequently accompanied by reduction in the ability of myocardium to generate force. This results in the clinical syndrome of heart failure, a major health problem worldwide. Despite the trigger event, heart failure is accompanied by structural alterations in myocardium such as myocyte hypertrophy, progressive myocyte loss and changes within the extracellular matrix, namely perivascular fibrosis around intramyocardial blood vessels and replacement fibrosis, which contribute to the progressive myocardial dysfunction and myocardial remodeling. It is conceivable that multiple stimuli and signaling mechanisms are involved in the determination of the phenotypic alterations of the myocardium during the remodeling and hypertrophic growth. Clinical and experimental evidence indicate that mechanical stimulus caused by hemodynamic overload plays a major role in the pathogenesis of these alterations. However, the mechanisms responsible for the transduction of mechanical stimuli into biochemical events are still poorly understood. Evidences, including those from our previous studies, indicate that the mechanical stimuli activate a complex signaling system composed by Integrin/Fak/Erk1/2, which could play a major role in the mechano-biochemical transduction in cardiac myocytes. Nevertheless, various aspect of this system, including its specific intracellular localization and its importance for gene expression and regulation in cardiac myocytes are still unknown. In addition, the contribution of this system for the structural alterations observed in response to chronic hemodynamic overload in the myocardium are also unknow. The aim of the studies in this research project is to explore signaling mechanisms activated by mechanical stimuli, with potential influence on the pathogenesis of structural and functional alterations observed in the myocardium during the development of cardiac hypertrophy and remodeling. The focus of the various studies is directed to better characterize the localization and function of the multicomponent signaling complex associated with Fak in cardiac myocytes, as well as its role in the pathogenesis of cardiac hypertrophy and remodeling. Additionally, in this research project studies were designed to develop tyrosine kinase inhibitors specific for Fak in order to better understand the importance of this enzyme on the phenotypic changes observed in overloaded myocardium, as well as to develop new strategies for the treatment of heart failure. Study I - Localization and activation of the multicomponent signaling complex associated with focal adhesion kinase (F AK) in the overloaded myocardium of rats... (AU)

Scientific publications

(12)

(The scientific publications listed on this page originate from the Web of Science or SciELO databases. Their authors have cited FAPESP grant or fellowship project numbers awarded to Principal Investigators or Fellowship Recipients, whether or not they are among the authors. This information is collected automatically and retrieved directly from those bibliometric databases.)

TORSONI, ADRIANA S.; CONSTANCIO, SABATA S.; NADRUZ JÚNIOR, WILSON; HANKS, STEVEN K.; FRANCHINI, KLEBER G.. Focal adhesion kinase is activated and mediates the early hypertrophic response to stretch in cardiac myocytes. Circulation Research, v. 93, n. 2, p. 140-147, July 2003. (01/11698-1)

NADRUZ JÚNIOR, WILSON; KOBARG, CLAUDIA B.; KOBARG, JORG; FRANCHINI, KLEBER G.. c-Jun is regulated by combination of enhanced expression and phosphorylation in acute-overloaded rat heart. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, v. 286, n. 2, p. H760-H767, Feb. 2004. (01/11698-1)

NADRUZ JÚNIOR, WILSON; CORAT, MARCUS A. F.; MARIN, TALITA M.; PEREIRA, GONÇALO A. GUIMARÃES; FRANCHINI, KLEBER G.. Focal adhesion kinase mediates MEF2 and c-Jun activation by stretch: role in the activation of the cardiac hypertrophic genetic program. Cardiovascular Research, v. 68, n. 1, p. 87-97, Oct. 2005. (01/11698-1)

CLEMENTE, CAROLINA F. M. Z.; TORNATORE, THAIS F.; THEIZEN, THAIS H.; DECKMANN, ANA C.; PEREIRA, TIAGO C.; LOPES-CENDES, ISCIA; SOUZA, JOSÉ ROBERTO M.; FRANCHINI, KLEBER G.. Targeting focal adhesion kinase with small interfering RNA prevents and reverses load-induced cardiac hypertrophy in mice. Circulation Research, v. 101, n. 12, p. 1339-1348, Dec. 2007. (01/11698-1)

NADRUZ‚ W.; LAGOSTA‚ V.J.; MORENO‚ H.; COELHO‚ O.R.; FRANCHINI‚ K.G.. Simvastatin prevents load-induced protein tyrosine nitration in overloaded hearts. Hypertension, v. 43, n. 5, p. 1060-1066, 2004. (01/11698-1)

LOPES‚ M.; RIBEIRO‚ G.; TORNATORE‚ T.; CLEMENTE‚ C.; TEIXEIRA‚ V.; FRANCHINI‚ K.. Increased expression and phosphorylation of focal adhesion kinase correlates with dysfunction in the volume-overloaded human heart. Clinical Science, v. 113, n. 3/4, p. 195-204, Aug. 2007. (01/11698-1)

FRANCHINI, KLEBER G.; MARIN, RODRIGO MIGUEL. Reduced oxygen supply explains the negative force-frequency relation and the positive inotropic effect of adenosine in buffer perfused hearts. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, v. 289, n. 1, p. H131-H136, July 2005. (01/11698-1)

CROSARA-ALBERTO, DANIELLA PEREIRA; INOUE, ROSANA YURI; CANTARELLI COSTA, CLAUDIA RAQUEL. FAK signalling mediates NF-kappa B activation by mechanical stress in cardiac myocytes. Clinica Chimica Acta, v. 403, n. 1-2, p. 81-86, MAY 2009. (01/11698-1)

NADRUZ JÚNIOR, WILSON; KOBARG, CLAUDIA B.; CONSTANCIO, SÁBATA S.; CORAT, PATRÍCIA D. C.; FRANCHINI, KLEBER G.. Load-induced transcriptional activation of c-jun in rat myocardium - Regulation by myocyte enhancer factor 2. Circulation Research, v. 92, n. 2, p. 243-251, Feb. 2003. (01/11698-1)

FONSECA, PRISCILA M.; INOUE, ROSANA Y.; KOBARG, CLAUDIA B.; CROSARA-ALBERTO, DANIELLA P.; KOBARG, JÖRG; FRANCHINI, KLEBER G.. Targeting to C-terminal myosin heavy chain may explain mechanotransduction involving focal adhesion kinase in cardiac myocytes. Circulation Research, v. 96, n. 1, p. 73-81, Jan. 2005. (01/11698-1)

TORSONI, ADRIANA S.; MARIN, TALITA M.; VELLOSO, LICIO A.; FRANCHINI, KLEBER G.. RhoA/ROCK signaling is critical to FAK activation by cyclic stretch in cardiac myocytes. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, v. 289, n. 4, p. H1488-H1496, Oct. 2005. (01/11698-1)

VELHO, JESUS ANTONIO; MARIN, RODRIGO MIGUEL; ROLIM FILHO, LUÍS DE ARRUDA; VERCESI, ANIBAL EUGÊNIO; RITTNER, ROBERTO; FRANCHINI, KLEBER GOMES; ROCCO, SILVANA APARECIDA. High performance liquid chromatography analysis of a 4-anilinoquinazoline derivative (PD153035), a specific inhibitor of the epidermal growth factor receptor tyrosine kinase, in rat plasma. JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES, v. 817, n. 2, p. 297-302, Mar. 2005. (01/11698-1)

Filed patent(s) as a result of this research project