Molecular mechanism controlling cardiac hypertrophy

Guido Tarone

The major interest of the laboratory is to investigate the molecular mechanism controlling cardiac hypertrophy.

We have identified Melusin, a muscle specific chaperone protein acting downstream of integrins, as key player in triggering adaptive cardiac response to different stress stimuli. Genetically modified mice lacking melusin expression fail to activate a compensatory cardiac hypertrophy program in response to stress conditions such as chronic pressure overload of the left ventricle (Brancaccio et al. 2003a). At the same time, forced expression of melusin in the heart of transgenic mice efficiently protects from left ventricle dilation and failure when heart is subjected to chronic pressure overload (De Acetis et al 2005) or to myocardial infarct (Unsöld et al. 2014). Melusin over−expression in the heart protects cardiomyocytes from apoptosis, prevents interstitial fibrosis deposition, reduces inflammation and promotes capillary vessel formation overall contributing to a compensatory remodeling of the cardiac tissue (De Acetis et al 2005). Melusin is reduced in hearts of human patients affected by dilated cardiomyopathy and reduction level parallels the functional cardiac impairment (Brokat et al 2007). Molecualr studies indicated that melusin coordinate the assembly of a molecular complex that includes the chaperone protein HSP90, the scaffold protein IQGAP1 and the three kinases Raf Mek and Erk leading to activation of the ERK signaling pathways (Sbroggiò et al. 2011a and b). Melusin also positively regulate activation of the AKT pathways in response to stress stimuli in the heart further contributing to compensatory cardiac remodeling (Tarone and Brancaccio 2015).

Based on these data, we are currently testing the therapeutic value of melusin gene therapy in animal affected by different forms of cardiomyopathies.


Selected Publications

Di Savino A, Panuzzo C, Rocca S, Familiari U, Piazza R, Crivellaro S, Carrà G, Ferretti R, Fusella F, Giugliano E, Camporeale A, Franco I, Miniscalco B, Cutrin JC, Turco E, Silengo L, Hirsch E, Rege-Cambrin G, Gambacorti-Passerini C, Pandolfi PP, Papotti M, Saglio G, Tarone G, Morotti A, Brancaccio M. Morgana acts as an oncosuppressor in chronic myeloid leukemia. Blood. 2015 Feb 12. pii:blood-2014-05-575001. [Epub ahead of print] PubMed PMID: 25678499.

Tarone G, Brancaccio M. The muscle-specific chaperone protein melusin is a potent cardioprotective agent. Basic Res Cardiol. 2015 Mar;110(2):10

Seano G, Chiaverina G, Gagliardi PA, di Blasio L, Puliafito A, Bouvard C, Sessa R, Tarone G, Sorokin L, Helley D, Jain RK, Serini G, Bussolino F, Primo L.  Endothelial podosome rosettes regulate vascular branching in tumour angiogenesis. Nat Cell Biol. 2014 Oct;16(10):931-41, 1-8. doi: 10.1038/ncb3036. Epub 2014 Sep 14. PubMed PMID: 25218639. 

Penna C, Brancaccio M, Tullio F, Rubinetto C, Perrelli MG, Angotti C, Pagliaro P, Tarone G. Overexpression of the muscle-specific protein, melusin, protects from cardiac ischemia/reperfusion injury. Basic Res Cardiol. 2014 Jul;109(4):418. doi: 10.1007/s00395-014-0418-9. Epub 2014 May 25. PubMed PMID: 24859929.  

Tarone G, Balligand JL, Bauersachs J, Clerk A, De Windt L, Heymans S, Hilfiker-Kleiner D, Hirsch E, Iaccarino G, Knöll R, Leite-Moreira AF, Lourenço AP, Mayr M, Thum T, Tocchetti CG. Targeting myocardial remodelling to develop novel therapies for heart failure: a position paper from the Working Group on Myocardial Function of the European Society of Cardiology. Eur J Heart Fail. 2014 May;16(5):494-508. doi: 10.1002/ejhf.62. Epub 2014 Mar 17. PubMed PMID: 24639064.  

Fusella F, Ferretti R, Recupero D, Rocca S, Di Savino A, Tornillo G, Silengo L, Turco E, Cabodi S, Provero P, Pandolfi PP, Sapino A, Tarone G, Brancaccio M. Morgana acts as a proto-oncogene through inhibition of a ROCK-PTEN pathway. J Pathol. 2014 Oct;234(2):152-63. doi: 10.1002/path.4341. Epub 2014 Aug 6. PubMed PMID: 24615293.  

Tarone G, Brancaccio M. Keep your heart in shape: molecular chaperone networks for treating heart disease. Cardiovasc Res. 2014 Jun 1;102(3):346-61. doi: 10.1093/cvr/cvu049. Epub 2014 Feb 28. PubMed PMID: 24585203. 

Leite-Moreira AF, Lourenço AP, Balligand JL, Bauersachs J, Clerk A, De Windt LJ, Heymans S, Hilfiker-Kleiner D, Hirsch E, Iaccarino G, Kaminski KA, Knöll R, Mayr M, Tarone G, Thum T, Tocchetti CG. ESC Working Group on Myocardial Function  Position Paper: how to study the right ventricle in experimental models. Eur J Heart Fail. 2014 May;16(5):509-18. doi: 10.1002/ejhf.66. Epub 2014 Feb 23. PubMed PMID: 24574252.  

Hohl M, Ardehali H, Azuaje FJ, Breckenridge RA, Doehner W, Eaton P, Ehret GB,  Fujita T, Gaetani R, Giacca M, Hasenfuß G, Heymans S, Leite-Moreira AF, Linke WA, Linz D, Lyon A, Mamas MA, Orešič M, Papp Z, Pedrazzini T, Piepoli M, Prosser B, Rizzuto R, Tarone G, Tian R, van Craenenbroeck E, van Rooij E, Wai T, Weiss G, Maack C. Meeting highlights from the 2013 European Society of Cardiology Heart Failure Association Winter Meeting on Translational Heart Failure Research. Eur J Heart Fail. 2014 Jan;16(1):6-14. doi: 10.1002/ejhf.10. Epub 2013 Dec 14. Review.  PubMed PMID: 24453095.  

Unsöld B, Kaul A, Sbroggiò M, Schubert C, Regitz-Zagrosek V, Brancaccio M, Damilano F, Hirsch E, Van Bilsen M, Munts C, Sipido K, Bito V, Detre E, Wagner NM, Schäfer K, Seidler T, Vogt J, Neef S, Bleckmann A, Maier LS, Balligand JL, Bouzin C, Ventura-Clapier R, Garnier A, Eschenhagen T, El-Armouche A, Knöll R, Tarone G, Hasenfuß G. Melusin protects from cardiac rupture and improves functional remodelling after myocardial infarction. Cardiovasc Res. 2014 Jan 1;101(1):97-107. doi: 10.1093/cvr/cvt235. Epub 2013 Oct 15. PubMed PMID: 24130190.  

Hirsch E, Hilfiker-Kleiner D, Balligand JL, Tarone G, De Windt L, Bauersachs J, Ferdinandy P, Davidson S, Hausenloy DJ, Schulz R. Interaction of the heart and its close and distant neighbours: report of the Meeting of the ESC Working Groups Myocardial Function and Cellular Biology. Cardiovasc Res. 2013 Sep 1;99(4):595-9. doi: 10.1093/cvr/cvt179. Epub 2013 Jul 16. PubMed PMID: 23860811.  

Tarone G, Sbroggiò M, Brancaccio M. Key role of ERK1/2 molecular scaffolds in heart pathology. Cell Mol Life Sci. 2013 Nov;70(21):4047-54. doi: 10.1007/s00018-013-1321-5. Epub 2013 Mar 27. Review. PubMed PMID: 23532408.  

Brizzi MF, Tarone G, Defilippi P. Extracellular matrix, integrins, and growth factors as tailors of the stem cell niche. Curr Opin Cell Biol. 2012 Oct;24(5):645-51. doi: 10.1016/ Epub 2012 Aug 13. Review. PubMed PMID: 22898530.  

Ferretti R, Sbroggiò M, Di Savino A, Fusella F, Bertero A, Michowski W, Tarone G, Brancaccio M. Morgana and melusin: two fairies chaperoning signal transduction. Cell Cycle. 2011 Nov 1;10(21):3678-83. doi: 10.4161/cc.10.21.18202. Epub 2011 Nov 1. Review. PubMed PMID: 22037254.  

Sbroggiò M, Bertero A, Velasco S, Fusella F, De Blasio E, Bahou WF, Silengo L, Turco E, Brancaccio M, Tarone G. ERK1/2 activation in heart is controlled by melusin, focal adhesion kinase and the scaffold protein IQGAP1. J Cell Sci. 2011  Oct 15;124(Pt 20):3515-24. doi: 10.1242/jcs.091140. PubMed PMID: 22010199; PubMed Central PMCID: PMC3706035.  

Knöll R, Iaccarino G, Tarone G, Hilfiker-Kleiner D, Bauersachs J, Leite-Moreira AF, Sugden PH, Balligand JL; European Society of Cardiology. Towards a re-definition of 'cardiac hypertrophy' through a rational characterization of left ventricular phenotypes: a position paper of the Working  Group 'Myocardial Function' of the ESC. Eur J Heart Fail. 2011 Aug;13(8):811-9. doi: 10.1093/eurjhf/hfr071. Epub 2011 Jun 27. PubMed PMID: 21708908.  

Sbroggiò M, Carnevale D, Bertero A, Cifelli G, De Blasio E, Mascio G, Hirsch E, Bahou WF, Turco E, Silengo L, Brancaccio M, Lembo G, Tarone G. IQGAP1 regulates ERK1/2 and AKT signaling in the heart and sustains functional remodeling upon pressure overload. Cardiovasc Res. 2011 Apr 14. [Epub ahead of print] PubMed PMID: 21493702.

Palumbo V, Segat L, Padovan L, Amoroso A, Trimarco B, Izzo R, Lembo G, Regitz-Zagrosek V, Knoll R, Brancaccio M, Tarone G, Crovella S. Melusin gene (ITGB1BP2) nucleotide variations study in hypertensive and cardiopathic patients. BMC Med Genet. 2009 Dec 17;10:140.

Sbroggiò M, Ferretti R, Percivalle E, Gutkowska M, Zylicz A, Michowski W, Kuznicki J, Accornero F, Pacchioni B, Lanfranchi G, Hamm J, Turco E, Silengo L, Tarone G, Brancaccio M. The mammalian CHORD-containing protein melusin is a stress response protein interacting with Hsp90 and Sgt1. FEBS Lett. 2008 Jun 11;582(13):1788-94.

Brokat S, Thomas J, Herda LR, Knosalla C, Pregla R, Brancaccio M, Accornero F, Tarone G, Hetzer R, Regitz-Zagrosek V. Altered melusin expression in the hearts of aortic stenosis patients. Eur J Heart Fail. 2007 Jun-Jul;9(6-7):568-73.

Brancaccio M, Hirsch E, Notte A, Selvetella G, Lembo G, Tarone G. Integrin signalling: the tug-of-war in heart hypertrophy. Cardiovasc Res. 2006 Jun 1;70(3):422-33.

Vecchione C, Aretini A, Marino G, Bettarini U, Poulet R, Maffei A, Sbroggiò M, Pastore L, Gentile MT, Notte A, Iorio L, Hirsch E, Tarone G, Lembo G. Selective Rac-1 inhibition protects from diabetes-induced vascular injury. Circ Res. 2006 Feb 3;98(2):218-25.

De Acetis M, Notte A, Accornero F, Selvetella G, Brancaccio M, Vecchione C, Sbroggiò M, Collino F, Pacchioni B, Lanfranchi G, Aretini A, Ferretti R, Maffei A, Altruda F, Silengo L, Tarone G, Lembo G. Cardiac overexpression of melusin protects from dilated cardiomyopathy due to long-standing pressure overload. Circ Res. 2005 May 27;96(10):1087-94.

Vecchione C, Patrucco E, Marino G, Barberis L, Poulet R, Aretini A, Maffei A, Gentile MT, Storto M, Azzolino O, Brancaccio M, Colussi GL, Bettarini U, Altruda F, Silengo L, Tarone G, Wymann MP, Hirsch E, Lembo G. Protection from angiotensin II-mediated vasculotoxic and hypertensive response in mice lacking PI3Kgamma. J Exp Med. 2005 Apr 18;201(8):1217-28.

Selvetella G, Hirsch E, Notte A, Tarone G, Lembo G. Adaptive and maladaptive  hypertrophic pathways: points of convergence and divergence. Cardiovasc Res. 2004 Aug 15;63(3):373-80. Review.

Tarone G, Lembo G. Molecular interplay between mechanical and humoral signalling in cardiac hypertrophy. Trends Mol Med. 2003 Sep;9(9):376-82. Review.

Brancaccio M, Fratta L, Notte A, Hirsch E, Poulet R, Guazzone S, De Acetis M,  Vecchione C, Marino G, Altruda F, Silengo L, Tarone G, Lembo G. Melusin, a muscle-specific integrin beta1-interacting protein, is required to prevent cardiac failure in response to chronic pressure overload. Nat Med. 2003 Jan;9(1):68-75.

Brancaccio M, Menini N, Bongioanni D, Ferretti R, De Acetis M, Silengo L, Tarone G. Chp-1 and melusin, two CHORD containing proteins in vertebrates. FEBS Lett. 2003 Sep 11;551(1-3):47-52.

Brancaccio M, Guazzone S, Menini N, Sibona E, Hirsch E, De Andrea M, Rocchi M, Altruda F, Tarone G, Silengo L. Melusin is a new muscle-specific interactor for beta(1) integrin cytoplasmic domain. J Biol Chem. 1999 Oct 8;274(41):29282-8.

Cabodi S, Tinnirello A, Bisaro B, Tornillo G, del Pilar Camacho-Leal M, Forni  G, Cojoca R, Iezzi M, Amici A, Montani M, Eva A, Di Stefano P, Muthuswamy SK, Tarone G, Turco E, Defilippi P. p130Cas is an essential transducer element in ErbB2 transformation. FASEB J. 2010 Oct;24(10):3796-808.

Michowski W, Ferretti R, Wisniewska MB, Ambrozkiewicz M, Beresewicz M, Fusella F, Skibinska-Kijek A, Zablocka B, Brancaccio M, Tarone G, Kuznicki J. Morgana/CHP-1 is a novel chaperone able to protect cells from stress. Biochim Biophys Acta. 2010 Sep;1803(9):1043-9.

Ferretti R, Palumbo V, Di Savino A, Velasco S, Sbroggiò M, Sportoletti P, Micale L, Turco E, Silengo L, Palumbo G, Hirsch E, Teruya-Feldstein J, Bonaccorsi S, Pandolfi PP, Gatti M, Tarone G, Brancaccio M. Morgana/chp-1, a ROCK inhibitor involved in centrosome duplication and tumorigenesis. Dev Cell. 2010 Mar 16;18(3):486-95.

Di Stefano P, Damiano L, Cabodi S, Aramu S, Tordella L, Praduroux A, Piva R, Cavallo F, Forni G, Silengo L, Tarone G, Turco E, Defilippi P. p140Cap protein suppresses tumour cell properties, regulating Csk and Src kinase activity. EMBO J. 2007 Jun 20;26(12):2843-55.

Boeri Erba E, Matthiesen R, Bunkenborg J, Schulze WX, Di Stefano P, Cabodi S,  Tarone G, Defilippi P, Jensen ON. Quantitation of multisite EGF receptor phosphorylation using mass spectrometry and a novel normalization approach. J Proteome Res. 2007 Jul;6(7):2768-85.

Cabodi S, Tinnirello A, Di Stefano P, Bisarò B, Ambrosino E, Castellano I, Sapino A, Arisio R, Cavallo F, Forni G, Glukhova M, Silengo L, Altruda F, Turco E, Tarone G, Defilippi P. p130Cas as a new regulator of mammary epithelial cell proliferation, survival, and HER2-neu oncogene-dependent breast tumorigenesis. Cancer Res. 2006 May 1;66(9):4672-80.

Ambrogio C, Voena C, Manazza AD, Piva R, Riera L, Barberis L, Costa C, Tarone G, Defilippi P, Hirsch E, Boeri Erba E, Mohammed S, Jensen ON, Palestro G, Inghirami G, Chiarle R. p130Cas mediates the transforming properties of the anaplastic lymphoma kinase. Blood. 2005 Dec 1;106(12):3907-16.
Defilippi P, Rosso A, Dentelli P, Calvi C, Garbarino G, Tarone G, Pegoraro L, Brizzi MF. {beta}1 Integrin and IL-3R coordinately regulate STAT5 activation and  anchorage-dependent proliferation. J Cell Biol. 2005 Mar 28;168(7):1099-108.

Di Stefano P, Cabodi S, Boeri Erba E, Margaria V, Bergatto E, Giuffrida MG, Silengo L, Tarone G, Turco E, Defilippi P. P130Cas-associated protein (p140Cap) as a new tyrosine-phosphorylated protein involved in cell spreading. Mol Biol Cell. 2004 Feb;15(2):787-800.

Giancotti FG, Tarone G. Positional control of cell fate through joint integrin/receptor protein kinase signaling. Annu Rev Cell Dev Biol. 2003;19:173-206. Review.