Cardiac‐Specific Disruption of Bin1 in Mice Enables a Model of Stress‐ and Age‐Associated Dilated Cardiomyopathy. Issue 11 (9th September 2015)

• Record Type: Journal Article
• Authors: Laury‐Kleintop, Lisa D.; Mulgrew, Jennifer R.; Heletz, Ido; Nedelcoviciu, Radu Alexandru; Chang, Mee Young; Harris, David M.; Koch, Walter J.; Schneider, Michael D.; Muller, Alexander J.; Prendergast, George C.
• Is Part Of: Journal of cellular biochemistry. Volume 116:Issue 11(2015:Nov.)
• Page Start: 2541
• Page End: 2551
• Publication Date: 2015-09-09
• Subjects: Cytochemistry -- Periodicals; 572
• DOI: 10.1002/jcb.25198
• Languages: English
• ISSNs: 0730-2312

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>ABSTRACT</title> <sec id="jcb25198-sec-0001" sec-type="section"> <p>Non‐compensated dilated cardiomyopathy (DCM) leading to death from heart failure is rising rapidly in developed countries due to aging demographics, and there is a need for informative preclinical models to guide the development of effective therapeutic strategies to prevent or delay disease onset. In this study, we describe a novel model of heart failure based on cardiac‐specific deletion of the prototypical mammalian BAR adapter‐encoding gene <italic>Bin1</italic>, a modifier of age‐associated disease. <italic>Bin1</italic> deletion during embryonic development causes hypertrophic cardiomyopathy and neonatal lethality, but there is little information on how <italic>Bin1</italic> affects cardiac function in adult animals. Here we report that cardiomyocyte‐specific loss of <italic>Bin1</italic> causes age‐associated dilated cardiomyopathy (DCM) beginning by 8–10 months of age. Echocardiographic analysis showed that <italic>Bin1</italic> loss caused a 45% reduction in ejection fraction during aging. Younger animals rapidly developed DCM if cardiac pressure overload was created by transverse aortic constriction. Heterozygotes exhibited an intermediate phenotype indicating <italic>Bin1</italic> is haplo‐insufficient to sustain normal heart function. <italic>Bin1</italic> loss increased left ventricle (LV) volume and diameter during aging, but it did not alter LV volume or diameter in hearts from heterozygous mice nor did it affect LV mass. <italic>Bin1</italic> loss increased interstitial fibrosis and mislocalization of the voltage‐dependent calcium channel Ca<sub>v</sub>1.2, and the lipid raft scaffold protein caveolin‐3, which normally complexes with Bin1 and Ca<sub>v</sub>1.2 in cardiomyocyte membranes. Our findings show how cardiac deficiency in Bin1 function causes age‐ and stress‐associated heart failure, and they establish a new preclinical model of this terminal cardiac disease. J. Cell. Biochem. 116: 2541–2551, 2015. © 2015 Wiley Periodicals, Inc.</p> </sec> </abstract>