Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 298, Issue 2, Pages H424-H432Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00529.2009
Keywords
cardiac hypertrophy; Smad protein; myofibroblast; extracellular matrix
Funding
- National Heart, Lung, and Blood Institute [HL-080017, HL-044195, HL-07457, HL-75211]
- Cardiovascular Pathophysiology Predoctoral Training [T32 HL-007918]
- American Heart Association Greater Southeast Affiliate [0455197B, 0425455B, 0765398B]
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Lucas JA, Zhang Y, Li P, Gong K, Miller AP, Hassan E, Hage F, Xing D, Wells B, Oparil S, Chen Y-F. Inhibition of transforming growth factor-beta signaling induces left ventricular dilation and dysfunction in the pressure-overloaded heart. Am J Physiol Heart Circ Physiol 298: H424-H432, 2010. First published November 20, 2009; doi:10.1152/ajpheart.00529.2009.-This study utilized a transgenic mouse model that expresses an inducible dominant-negative mutation of the transforming growth factor (TGF)-beta type II receptor (DnTGF beta RII) to define the structural and functional responses of the left ventricle (LV) to pressure-overload stress in the absence of an intact TGF-beta signaling cascade. DnTGF beta RII and nontransgenic (NTG) control mice (male, 8-10 wk) were randomized to receive Zn2+ (25 mM ZnSO4 in drinking H2O to induce DnTGF beta RII gene expression) or control tap H2O and then further randomized to undergo transverse aortic constriction (TAC) or sham surgery. At 7 days post-TAC, interstitial nonmyocyte proliferation (Ki67 staining) was greatly reduced in LV of DnTGF beta RII + Zn2+ mice compared with the other TAC groups. At 28 and 120 days post-TAC, collagen deposition (picrosirius-red staining) in LV was attenuated in DnTGF beta RII + Zn2+ mice compared with the other TAC groups. LV end systolic diameter and end systolic and end diastolic volumes were markedly increased, while ejection fraction and fractional shortening were significantly decreased in TAC-DnTGF beta RII + Zn2+ mice compared with the other groups at 120 days post-TAC. These data indicate that interruption of TGF-beta signaling attenuates pressure-overload-induced interstitial nonmyocyte proliferation and collagen deposition and promotes LV dilation and dysfunction in the pressure-overloaded heart, thus creating a novel model of dilated cardiomyopathy.
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