Heart failure, a major health problem, appears most commonly in patients with previous myocardial infarction (MI). Fibrosis is considered a major component of adverse structural remodeling found in ischemic cardiomyopathy. Myofibroblasts (myoFbs), phenotypically transformed fibroblast-like cells, are responsible for fibrogenesis and extracellular matrix remodeling following MI. MyoFbs have characteristics intermediate between fibroblasts (e.g., collagen synthesis) and smooth muscle cells (e.g., alpha-smooth muscle actin, ASMA) and they create a dynamic microenvironment. Repair postMI involves an initial combination of matrix degradation, cell growth and spatial control of growth followed by collagen synthesis and deposition.
Our first aim i s to identify and characterize myoFb progenitors and signals following MI by i) determining whether circulating fibrocytes (Fcs) or interstitial fibroblasts (IFbs) are progenitors of myoFb by tagging isolated Fcs ex vivo with beta-galactosidase gene, intravenous injection of tagged Fcs and monitoring their appearance at the infarct site, and ii) studying the role of signalling molecules such as NF-kappaB, TGF-beta1 and tyrosine kinases that activate MMP-1. In our second aim, we will determine the role of tissue polarity gene frizzled 2 (fz2) on spatial control of myoFb alignment and factors involved in myoFb-derived fibrous tissue formation by i) studying fz2 and wnt gene expression in the infarcted heart, ii) addressing fz2 expression in infarct expansion and ventricular aneurysm, and iii) identifying factors regulating myoFb matrix deposition.
Our third aim i s to determine mechanisms of myoFb persistence and their fibrogenic activity by i) studying signals responsible for continuous generation vs persistence of a particular myoFb phenotype and their collagen turnover, ii) determining the role of proapoptotic genes such as Bax and inhibitors of apoptosis, such as Bc12 on myoFb persistence, and iii) determining the role of ventricular unloading (stress relaxation) on myoFb fate, phenotype and activity. Finally, we extrapolate these observations to human hearts with ischemic cardiomyopathy. Insights into these fundamental questions of tissue repair will contribute to prospects for protective interventions that will enable effective management of heart failure of ischemic origin.
|Sun, Yao; Weber, Karl T (2005) Animal models of cardiac fibrosis. Methods Mol Med 117:273-90|
|Chhokar, Vikram S; Sun, Yao; Bhattacharya, Syamal K et al. (2005) Hyperparathyroidism and the calcium paradox of aldosteronism. Circulation 111:871-8|
|Wang, Bin; Ansari, Ramin; Sun, Yao et al. (2005) The scar neovasculature after myocardial infarction in rats. Am J Physiol Heart Circ Physiol 289:H108-13|
|Chhokar, Vikram S; Sun, Yao; Bhattacharya, Syamal K et al. (2004) Loss of bone minerals and strength in rats with aldosteronism. Am J Physiol Heart Circ Physiol 287:H2023-6|
|Sun, Yao; Zhang, Jiakun; Lu, Li et al. (2004) Tissue angiotensin II in the regulation of inflammatory and fibrogenic components of repair in the rat heart. J Lab Clin Med 143:41-51|
|Ahokas, Robert A; Warrington, Kenneth J; Gerling, Ivan C et al. (2003) Aldosteronism and peripheral blood mononuclear cell activation: a neuroendocrine-immune interface. Circ Res 93:e124-35|
|Gerling, Ivan C; Sun, Yao; Ahokas, Robert A et al. (2003) Aldosteronism: an immunostimulatory state precedes proinflammatory/fibrogenic cardiac phenotype. Am J Physiol Heart Circ Physiol 285:H813-21|