Pathogenesis of cardiac hypertrophy and failure: mechanisms activated by mechanical stress

• Grant number: 06/54878-3
• Support type: Research Projects - Thematic Grants
• Duration: July 01, 2007 - September 30, 2011
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal researcher: Kleber Gomes Franchini
• Grantee: Kleber Gomes Franchini
• Home Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated scholarship(s): 11/01356-8 - Functional and Structural Analysis of the Cardiac Proteins Associated to the Z Disc, Calsarcin and Enigma, BP.DR; 11/01538-9 - Structural Studies of Shp2 mutants, BP.PD; 10/17086-7 - Investigation of cellular localization focal adhesion kinase (FAK) and mutant FAK (FAKY397F) in cardiomiocytes in vitro and in genetically modified mice, BP.DR; + associated scholarships 09/17597-4 - Characterization of new target genes of the transcription factors MEF2 in cardiomyocytes, BP.DD; 09/17598-0 - Identification of FAK nuclear-binding proteins in cardiac myocytes., BP.DR; 08/57629-0 - New 2,8-disubstituted quinazolines with potential inhibitory activity of focal adhesion kinase (FAK), BP.DR - associated scholarships

Abstract

The most prevalent heart diseases (e.g. hypertensive, ischemic) increase the mass (i.e. hypertrophy) and change the shape (i.e. remodeling) of left ventricle. These changes are paralleled by complex and progressive alterations in the myocardial structure, featured by hypertrophy and degeneration of cardiac myocytes and interstitial fibrosis. The impairment of myocardial function that accompanies these structural abnormalities culminates in heart failure. Chronic increase in the mechanical load is a critical determinant of the myocardial structural abnormalities, mainly cardiac myocytes hypertrophy. A great deal of effort has been devoted to finding signaling mechanisms involved in the responses of cardiac myocytes to mechanical forces. It is expected that the identification of such mechanisms will provide novel therapeutic opportunities to cardiac hypertrophy and failure. In a similar manner, understanding the molecular logic of hypertrophy and heart failure will ultimately require forming mechanistic connections between defined clinical disease surrogates with specific positive and negative molecular checkpoints that arise at specific stages during the natural temporal progression of this chronic disease. The studies of our laboratory have been directed to these two major frontiers. We have previously demonstrated the critical role of a signaling network that includes FAK (focal adhesion kinase) and the transcription factors of the MEF2 family, as mediators of the phenotypic alterations of cardiac myocytes in response to mechanical stress. In the clinic ¬pathophysiological scenario we have shown the early functional deterioration of the hypertrophic myocardium in hypertensive subjects, and the reversibility of the unfavorable clinical and prognostic indices in response to mechanical unloading produced by left ventricular reconstruction in patients with heart failure after myocardial infarction. Our present proposal includes 10 sub-projects devoted 1) to study the molecular mechanisms of FAK activation by mechanical stress; 2) to study the effects of RNA interference specific to FAK and other signaling molecules (SHP2, αB-Cristalina e MEF2) possibly involved in the mechanic¬ transduction in cardiac myocytes; 3) to study the molecular mechanisms coordinated by FAK in the transcriptional regulation in cardiac myocytes; 4) to find compounds that might potentially inhibit FAK activity; 5) to determine FAK expression and activity in the remote areas of the left ventricle in patients with chronic myocardial infarction and correlate such findings with clinical evolution after left ventricular reconstruction surgery; and 6) to determine the mechanisms responsible for the early functional alterations in the left ventricle of hypertensive patients. (AU)

Scientific publications

(9)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

PEREIRA, MICHELLE B. M.; SANTOS, ALINE M.; GONCALVES, DANIELI C.; CARDOSO, ALISSON C.; CONSONNI, SILVIO R.; GOZZO, FABIO C.; OLIVEIRA, PAULO S.; PEREIRA, ANA HELENA M.; FIGUEIREDO, ALANA R.; TIROLI-CEPEDA, ANA O.; RAMOS, CARLOS H. I.; DE THOMAZ, ANDRE A.; CESAR, CARLOS L.; FRANCHINI, KLEBER G. alpha B-crystallin interacts with and prevents stress-activated proteolysis of focal adhesion kinase by calpain in cardiomyocytes. NATURE COMMUNICATIONS, v. 5, OCT 2014. Web of Science Citations: 16.

CLEMENTE, C. F. M. Z.; XAVIER-NETO, J.; COSTA, A. P. DALLA; CONSONNI, S. R.; ANTUNES, J. E.; ROCCO, S. A.; PEREIRA, M. B.; JUDICE, C. C.; STRAUSS, B.; JOAZEIRO, P. P.; MATOS-SOUZA, J. R.; FRANCHINI, K. G. Focal adhesion kinase governs cardiac concentric hypertrophic growth by activating the AKT and mTOR pathways. JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, v. 52, n. 2, SI, p. 493-501, FEB 2012. Web of Science Citations: 37.

FRANCHINI, K. G. Focal adhesion kinase - The basis of local hypertrophic signaling domains. JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, v. 52, n. 2, SI, p. 485-492, FEB 2012. Web of Science Citations: 29.

SANTOS, ALINE M.; SCHECHTMAN, DEBORAH; CARDOSO, ALISSON C.; CLEMENTE, CAROLINA F. M. Z.; SILVA, JULIO C.; FIORAMONTE, MARIANA; PEREIRA, MICHELLE B. M.; MARIN, TALITA M.; OLIVEIRA, PAULO S. L.; FIGUEIRA, ANA CAROLINA M.; OLIVEIRA, SAULO H. P.; TORRIANI, IRIS L.; GOZZO, FABIO C.; NETO, JOSE XAVIER; FRANCHINI, KLEBER G. FERM domain interaction with myosin negatively regulates FAK in cardiomyocyte hypertrophy. Nature Chemical Biology, v. 8, n. 1, p. 102-110, JAN 2012. Web of Science Citations: 14.

DALLA COSTA, ANA PAULA; CLEMENTE, CAROLINA F. M. Z.; CARVALHO, HERNANDES F.; CARVALHEIRA, JOSE B.; NADRUZ, JR., WILSON; FRANCHINI, KLEBER G. RETRACTED: FAK mediates the activation of cardiac fibroblasts induced by mechanical stress through regulation of the mTOR complex (Retracted article. See vol. 104, pg. 512, 2014). Cardiovascular Research, v. 86, n. 3, p. 421-431, JUN 1 2010. Web of Science Citations: 37.

K.G. FRANCHINI; C.F.M.Z. CLEMENTE; T.M. MARIN. Focal adhesion kinase signaling in cardiac hypertrophy and failure. Brazilian Journal of Medical and Biological Research, v. 42, n. 1, p. 44-52, Jan. 2009.

DE OLIVEIRA, MICHEL V.; MARIN, TALITA M.; CLEMENTE, CAROLINA F.; DALLA COSTA, ANA PAULA; JUDICE, CARLA C.; FRANCHINI, KLEBER G. SHP-2 regulates myogenesis by coupling to FAK signaling pathway. FEBS Letters, v. 583, n. 18, p. 2975-2981, 2009. Web of Science Citations: 11.

PEREIRA, ANA HELENA M.; CLEMENTE, CAROLINA F. M. Z.; CARDOSO, ALISSON C.; THEIZEN, THAIS H.; ROCCO, SILVANA A.; JUDICE, CARLA C.; GUIDO, MARIA CAROLINA; PASCOAL, VINICIUS D. B.; LOPES-CENDES, ISCIA; SOUZA, JOSE ROBERTO M.; FRANCHINI, KLEBER G. MEF2C Silencing Attenuates Load-Induced Left Ventricular Hypertrophy by Modulating mTOR/S6K Pathway in Mice. PLoS One, v. 4, n. 12, p. e8472, 2009. Web of Science Citations: 22.

MARIN, TALITA M.; CLEMENTE, CAROLINA F. M. Z.; SANTOS, ALINE M.; PICARDI, PATY K.; PASCOAL, VINICIUS D. B.; LOPES-CENDES, ISCIA; SAAD, MARIO J. A.; FRANCHINI, KLEBER G. Shp2 negatively regulates growth in cardiomyocytes by controlling focal adhesion kinase/Src and mTOR pathways. Circulation Research, v. 103, n. 8, p. 813-U90, OCT 10 2008. Web of Science Citations: 40.