Author(s)

Feng Bai¹, Guangzhao Yang¹, Joshua Robert Eskew², Ningping Wang², Himangshu Bose², Zhiqing Zhao^1,2*

¹Department of Cardiology, The First Affiliated Hospital of Shanxi Medical University, Taiyuan, China.
²Cardiovascular Research Laboratory, School of Medicine, Mercer University, Savannah, GA, USA.

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 < 0.05 vs. unstimulated cells), but these changes were significantly downregulated by the AT1 receptor blocker, telmisartan (all p < 0.05 vs. Ang II activated cells). Furthermore, mRNA and protein level of CD44 were upregulated, and there was a linear correlation between CD44 and TGF-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.

Angiotensin II AT1 Receptor, CD44, Collagen, Fibroblasts, Telmisartan

Bai, F. , Yang, G. , Eskew, J. , Wang, N. , Bose, H. and Zhao, Z. (2020) Antagonism of Angiotensin II AT1 Receptor and Silencing of CD44 Gene Expression Inhibit Cardiac Fibroblast Activation via Modulating TGF-β1/Smad Signaling Pathway. Advances in Bioscience and Biotechnology, 11, 123-139. doi: 10.4236/abb.2020.114010.