Abnormal muscle mechanosignaling triggers cardiomyopathy in mice with Marfan syndrome

Jason R. Cook, Luca Carta, Ludovic Bénard, Elie R. Chemaly, Emily Chiu, Satish K. Rao, Thomas G. Hampton, Peter Yurchenco, Kevin D. Costa, Roger J. Hajjar, Francesco Ramirez

Research output: Contribution to journalArticlepeer-review

82 Scopus citations

Abstract

Patients with Marfan syndrome (MFS), a multisystem disorder caused by mutations in the gene encoding the extracellular matrix (ECM) protein fibrillin 1, are unusually vulnerable to stress-induced cardiac dysfunction. The prevailing view is that MFS-associated cardiac dysfunction is the result of aortic and/or valvular disease. Here, we determined that dilated cardiomyopathy (DCM) in fibrillin 1-deficient mice is a primary manifestation resulting from ECM-induced abnormal mechanosignaling by cardiomyocytes. MFS mice displayed spontaneous emergence of an enlarged and dysfunctional heart, altered physical properties of myocardial tissue, and biochemical evidence of chronic mechanical stress, including increased angiotensin II type I receptor (AT1R) signaling and abated focal adhesion kinase (FAK) activity. Partial fibrillin 1 gene inactivation in cardiomyocytes was sufficient to precipitate DCM in otherwise phenotypically normal mice. Consistent with abnormal mechanosignaling, normal cardiac size and function were restored in MFS mice treated with an AT1R antagonist and in MFS mice lacking AT1R or β-arrestin 2, but not in MFS mice treated with an angiotensin-converting enzyme inhibitor or lacking angiotensinogen. Conversely, DCM associated with abnormal AT1R and FAK signaling was the sole abnormality in mice that were haploinsufficient for both fibrillin 1 and β1 integrin. Collectively, these findings implicate fibrillin 1 in the physiological adaptation of cardiac muscle to elevated workload.

Original languageEnglish (US)
Pages (from-to)1329-1339
Number of pages11
JournalJournal of Clinical Investigation
Volume124
Issue number3
DOIs
StatePublished - Mar 3 2014
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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