Reduced vasorin enhances angiotensin II signaling within the aging arterial wall
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Gianfranco Pintus1,2,*, Roberta Giordo1,2,*, Yushi Wang1,3, Wanqu Zhu1, Soo Hyuk Kim1, Li Zhang1,4, Leng Ni1,5, Jing Zhang1, Richard Telljohann1, Kimberly R. McGraw1, Robert E. Monticone1, Chloe Ferris1, Lijuan Liu1, Mingyi Wang1 and Edward G. Lakatta1
1Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Biomedical Research Center (BRC), Baltimore, MD, USA
2Biomedical Research Center, Qatar University, Doha, Qatar
3Department of Cardiology, The First Hospital of Jilin University, Changchun, China
4Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China
5Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
*These authors have contributed equaly to this work
Mingyi Wang, email: [email protected]
Keywords: aging; arterial remodeling; VSMC; vasorin; collagen
Received: August 09, 2017 Accepted: May 10, 2018 Published: June 05, 2018
The glycosylated protein vasorin physically interacts with the transforming growth factor-beta1 (TGF-β1) and functionally attenuates its fibrogenic signaling in the vascular smooth muscle cells (VSMCs) of the arterial wall. Angiotensin II (Ang II) amplifies TGF-β1 activation in the VSMCs of the arterial wall with aging. In this study, we hypothesized that a reduced expression of the protein vasorin plays a contributory role in magnifying Ang II-associated fibrogenic signaling in the VSMCs of the arterial wall with aging. The current study shows that vasorin mRNA and protein expression were significantly decreased both in aortic wall and VSMCs from old (30 mo) vs. young (8 mo) FXBN rats. Exposing young VSMCs to Ang II reduced vasorin protein expression to the levels of old untreated cells while treating old VSMCs with the Ang II type AT1 receptor antagonist Losartan upregulated vasorin protein expression up to the levels of young. The physical interaction between vasorin and TGF-β1 was significantly decreased in old vs. young VSMCs. Further, exposing young VSMCs to Ang II increased the levels of matrix metalloproteinase type II (MMP-2) activation and TGF-β1 downstream molecules p-SMAD-2/3 and collagen type I production up to the levels of old untreated VSMCs, and these effects were substantially inhibited by overexpressing vasorin. Administration of Ang II to young rats (8 mo) for 28 days via an osmotic minipump markedly reduced the expression of vasorin. Importantly, vasorin protein was effectively cleaved by activated MMP-2 both in vitro and in vivo. Administration of the MMP inhibitor, PD 166793, for 6 mo to young adult (18 mo) via a daily gavage markedly increased levels of vasorin in the aortic wall. Thus, reduced vasorin amplifies Ang II profibrotic signaling via an activation of MMP-2 in VSMCs within the aging arterial wall.
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