Abstract 11841: Activation of Cardiac Fibulin-4 Protects Against Pressure Overload-Induced Cardiac Hypertrophy and Heart Failure

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Cutis laxa is a rare disorder caused by mutations in the extracellular matrix (ECM) protein Fibulin-4 and patients are susceptible to stress-induced cardiac dysfunction. Mice with a 75% reduction in Fibulin-4 expression (Fibulin-4 R/R ) developed cardiac hypertrophy, dilation and dysfunction as well as aortic aneurysms. The prevailing view is that this is the result of aortic and/or valvular disease, given that Fibulin-4 is believed to be exclusively involved in arterial and valvular elastogenesis and collagen deposition. Yet mortality after cardiac pressure-overload through transverse aortic constriction (TAC) was also increased in haploinsufficient Fibulin-4 +/R mice with a 50% reduced Fibulin-4 expression compared to wildtype animals. To determine whether the TAC-induced dilated cardiomyopathy in haploinsufficient Fibulin-4 +/R mice is a primary manifestation resulting from ECM abnormalities we analyzed the hearts of these mice for the presence of Fibulin-4 expression. Fibulin-4 expression was found to be activated throughout the entire myocardium in TAC-exposed wildtype animals. TAC-exposed Fibulin-4 +/R animals did not show this strong increase in myocardial Fibulin-4 expression but displayed emergence of altered physical properties of myocardial tissue, and biochemical evidence of chronic mechanical stress, including decreased focal adhesion kinase activity similar to TAC-exposed wildtype animals. Moreover, reduced Fibulin-4 expression aggravated TAC-induced cardiac fibrosis and pulmonary congestion. In microtissues derived from neonatal Fibulin-4 deficient hearts, Fibulin-4 deficiency decreased the beating frequency and contractile force of microtissues. It also reduced the maximal force-generating capacity of single membrane-permeabilized cardiomyocytes. Our findings demonstrate novel functions for Fibulin-4 in cardiac homeostasis, and show that reduced Fibulin-4 expression drives myocardial disease in response to cardiac pressure overload independent of aortic valvular pathology. These so far unrecognized effects of Fibulin-4 on myocardial function could have important implications both for patients with connective tissue disorders and for the general population in response to pressure overload.

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