Thyroid hormone receptor-beta is associated with coronary angiogenesis during pathological cardiac hypertrophy.
Insufficient angiogenesis is one of the causes leading to tissue ischemia and dysfunction. In heart failure, there is increasing evidence showing decreased capillary density in the left ventricle (LV) myocardium, although the detailed mechanisms contributing to it are not clear. The goal of this study was to investigate the role of thyroid hormone receptors (TRs) in the coronary microvascular rarefaction under pathological cardiac hypertrophy. The LV from hypertrophied/failing hearts induced by ascending aortic constriction (AAC) exhibited severe microvascular rarefaction, and this phenomenon was restored by chronic T(3) administration. Coronary endothelial cells (ECs) isolated from AAC hearts expressed lower TRbeta mRNA than control ECs, and chronic T(3) administration restored TRbeta mRNA expression level in AAC hearts to the control level. Among different TR subtype-specific knockout mice, TRbeta knockout and TRalpha/TRbeta double-knockout mice both exhibited significantly less capillary density in LV compared with wild-type mice. In vitro, coronary ECs isolated from TRbeta knockout mice lacked the ability to form capillary networks. In addition, we identified that kinase insert domain protein receptor/fetal liver kinase-1 (vascular endothelial growth factor-2 receptor) was one of the angiogenic mediators controlled by T(3) administration in the AAC heart. These data suggest that TRbeta in the coronary ECs regulates capillary density during cardiac development, and down-regulation of TRbeta results in coronary microvascular rarefaction during pathological hypertrophy.
Makino
Ayako
A
Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California 92093-0618, USA. wdillmann@ucsd.edu.
Suarez
Jorge
J
Wang
Hong
H
Belke
Darrell D
DD
Scott
Brian T
BT
Dillmann
Wolfgang H
WH
D000818:Animals; D015153:Blotting, Western; D006332:Cardiomegaly / Q000378:metabolism*; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D037042:Thyroid Hormone Receptors beta / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D014284:Triiodothyronine / Q000494:pharmacology
D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine