Cardiac-specific disruption of Bin1 in mice enables a model of stress- and age-associated dilated cardiomyopathy.
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 Bin1, a modifier of age-associated disease. Bin1 deletion during embryonic development causes hypertrophic cardiomyopathy and neonatal lethality, but there is little information on how Bin1 affects cardiac function in adult animals. Here we report that cardiomyocyte-specific loss of Bin1 causes age-associated dilated cardiomyopathy (DCM) beginning by 8-10 months of age. Echocardiographic analysis showed that Bin1 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 Bin1 is haplo-insufficient to sustain normal heart function. Bin1 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. Bin1 loss increased interstitial fibrosis and mislocalization of the voltage-dependent calcium channel Cav 1.2, and the lipid raft scaffold protein caveolin-3, which normally complexes with Bin1 and Cav 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.
Lankenau Institute for Medical Research, Wynnewood, Pennsylvania.
Lisa D
LD
Laury-Kleintop
Lankenau Institute for Medical Research, Wynnewood, Pennsylvania.
Jennifer R
JR
Mulgrew
Lankenau Medical Center, Wynnewood, Pennsylvania.
Ido
I
Heletz
Lankenau Medical Center, Wynnewood, Pennsylvania.
Radu Alexandru
RA
Nedelcoviciu
Lankenau Institute for Medical Research, Wynnewood, Pennsylvania.
Mee Young
MY
Chang
Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
David M
DM
Harris
Center for Translational Medicine, Temple University Medical School, Philadelphia, Pennsylvania.
Walter J
WJ
Koch
National Heart and Lung Institute, British Heart Foundation Centre of Research Excellence, Faculty of Medicine, Imperial College London, London, UK.
Michael D
MD
Schneider
Lankenau Institute for Medical Research, Wynnewood, Pennsylvania.
Alexander J
AJ
Muller
Lankenau Institute for Medical Research, Wynnewood, Pennsylvania.|Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical School and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
George C
GC
Prendergast
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency*; D000375:Aging / Q000235:genetics*; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000503:physiopathology; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000172:deficiency*; D009928:Organ Specificity; D013318:Stroke Volume; D025521:Tumor Suppressor Proteins / Q000172:deficiency*
D048868:Adaptor Proteins, Signal Transducing; C109221:Bin1 protein, mouse; D009419:Nerve Tissue Proteins; D025521:Tumor Suppressor Proteins
BAR ADAPTER; BAR DOMAIN; CARDIOMYOCYTE; CAVEOLIN; Cav1.2; DIHYDROPYRIDINE RECEPTOR (DHPR); LIPID RAFTS