Abstract 18881: Improper Elastic Fiber Assembly Drives Cardiac Pathology
Elastin is ubiquitously expressed in the cardiovascular system and essential for maintaining aortic wall integrity and function. Little is known however, about the role of elastin in the heart. To explore the influence of elastin on cardiac pathology we knocked down an essential protein for elastogenesis, fibulin-4, in human induced pluripotent stemcell (iPS)-derived cardiomyocytes. Strikingly, 90% reduction of fibulin-4 expression by shRNA, increased cardiomyocyte size by 35% and enhanced expression of atrial natriuretic peptide (ANP) and of TGFβ-regulated genes such as connective tissue growth factor and plasminogen activator inhibitor-1 in these cultured cardiomyocytes (all p<0.05). Accordingly, mice with a 75% reduction in fibulin-4 expression (Fibulin-4R/R), developed cardiac hypertrophy, dilation and dysfunction (ejection fraction [76±2 to 21±3 %]) as well as aortic aneurysms. This was accompanied by elevated myocardial TGFβ signalling and ANP, while expression of sarcoplasmic reticulum calcium transport ATPase and maximal force generating capacity of single membrane-permeabilized cardiomyocytes was reduced by 60% and 25%, respectively (both p<0.05). Subsequently, we explored the influence of fibulin-4 and elastogenesis on the development of cardiac pathology by subjecting mice with a 50% reduction in fibulin-4 expression (Fibulin-4+/R), without apparent cardiovascular abnormalities, to 4 weeks of transverse aortic constriction (TAC). Following TAC, mortality was markedly increased in Fibulin-4+/R animals compared to wildtype mice [20% to 84%; p<0.05]. Moreover, in surviving mice, reduced fibulin-4 expression aggravated TAC-induced LV systolic and diastolic dysfunction and pulmonary congestion without affecting valvular function. In conclusion, using gradually reductions in fibulin-4 expression in mice and iPS derived cardiomyocytes we show that improper elastic fiber assembly drives cardiac pathology.
- © 2013 by American Heart Association, Inc.