Thyroid hormone (TH) signaling in hypertrophic growth of the heart
04 / 2006 - onbekend
Thyroid hormone (TH) has profound effects on cardiac growth and differentiation. The established view, that enlargement of the adult heart in response to TH is due to cellular hypertrophy rather than proliferation, is challenged by recent evidence that progenitor cells (PCs) are capable of providing new cardiomyocytes (CMCs) in the hypertrophic, diseased heart. From our point of view physiological cardiac hypertrophy, as induced by TH, provides the most suitable model to clarify the basic mechanisms of activation and proliferation of cardiac cells. Therefore aim of this project is to assess the contribution of PCs, CMCs, and growth factors to hypertrophy of the hyperthyroid heart. The planned studies will investigate: (A) the specific contribution of activation and proliferation of cardiac cells in hypertrophy of the adult hyperthyroid heart; (B) how growth factor expression downstream of TH actions, i.e. insulin-like and fibroblast growth factor (IGF-1 and FGF-2) regulate PC activation and differentiation; (C) how TH affects local signaling pathways downstream of IGF-1 and FGF-2, thereby initiating proliferation and differentiation of cardiac cells. We developed a mouse model in which local heart and total body irradiation are used to prevent proliferation of cardiac PCs and bone-marrow derived PCs, respectively, allowing assessment of their contribution to TH-induced cardiac hypertrophy. This will be paralleled in vitro by examining the effects of TH on regulation of local growth factor signaling in cultured cardiac cells. New insights in the adaptive structural, functional and molecular rearrangements of the heart underlying physiological cardiac hypertrophy will improve the understanding of the regenerative capacity of the heart.