Abstract
Angiotensin II (Ang II) is known to elicit cardiac fibrosis by activating the AT1 receptor and CD44 expression in the in vivo model. However, the cellular/molecular mechanisms underlying cardiac fibrosis are still not well understood. This study examines the roles of the AT1 receptor and CD44 gene expression in collagen synthesis through Ang II stimulated cardiac fibroblasts. Fibroblasts were isolated from the neonatal rat hearts; the activation of fibroblasts was evaluated using the assays of cell viability and migration, and silencing of CD44 gene expression was conducted with small interfering RNA (siRNA). Results showed that Ang II significantly increases the cell proliferation and migration in a dose-dependent manner. Upon activation, the protein levels of TGF-β1, Smad2, Smad4 and collagen I were significantly increased (all p by the AT1 receptor blocker, telmisartan (all p β1 as demonstrated by Pearson correlation analysis (r = 0.955, p < 0.01). Gene transfection of fibroblasts with Ad-CD44 siRNA, as evidenced by low levels of CD44 mRNA and protein, significantly reduced the production of collagen I. In summary, these results indicate that the proliferation, migration and collagen production from Ang II activated cardiac fibroblasts are potentially mediated by the AT1 receptor and CD44. Such a signaling mechanism could be crucial for the production of collagen and the development of tissue fibrosis in the heart.
Highlights
Cardiac fibroblasts, defined as cells of the non-cardiomyocytes in the heart, are usually spindle-shaped cells with a large oval/flat pleomorphic nucleus, which can be found in the interstitial spaces of myocardium [1]
This study examines the roles of the AT1 receptor and CD44 gene expression in collagen synthesis through Angiotensin II (Ang II) stimulated cardiac fibroblasts
In the rat model of angiotensin II (Ang II) infusion, we have previously reported that the blockade of Ang II AT1 receptor with a selective AT1 receptor blocker telmisartan reduces myocardial fibrosis, which is primarily mediated by inhibiting differentiation of fibroblasts to myofibroblasts via downregulating the expression of transforming growth factor-β1 (TGF-β1) released from the infiltrated macrophages
Summary
Cardiac fibroblasts, defined as cells of the non-cardiomyocytes in the heart, are usually spindle-shaped cells with a large oval/flat pleomorphic nucleus, which can be found in the interstitial spaces of myocardium [1]. Cardiac fibroblasts provide a structural scaffold for cardiomyocytes by producing fibrillar collagens as the predominant components of extracellular matrix proteins to maintain the structural integrity of the heart [2] [3]. Upon mechanical or chemical injury to the myocardium, the population of cardiac fibroblasts increases through the replication of resident fibroblasts, transformation of endothelial cells or migration of bone marrow cells. In turn, produce excessive fibrotic extracellular matrix, and cause cardiac fibrosis and cardiomyocyte hypertrophy [8]
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