Abstract 14820: Sirt7 Deficiency in Blood Vessel Components Impairs Vascular Function by Inhibiting Cell Cycle- and Inflammatory-Related Protein Expression
Introduction: Aging is a well-established cardiovascular risk factor and associated with vascular dysfunction. Sirt7, one of the members of mammalian sirtuin family, is thought to be involved in age-related diseases. However, little is known about the relative contribution of Sirt7 in vascular dysfunction.
Hypothesis: Sirt7 maintains vascular cell functions and its deficiency plays a critical role in vascular diseases.
Methods: Sirt7 loss- and gain-of-function experiments were performed with human aortic smooth muscle cells (HAoSMCs) and human umbilical vein endothelial cells (HUVECs). In vivo, blood flow recovery was evaluated by hindlimb ischemia model in homozygous Sirt7 deficient (Sirt7-/-) and wild-type (WT) mice. Irradiated WT mice were intravenously received bone marrow (BM) cells from WT or Sirt7 -/- mouse to achieve BM transfer.
Results: An RNAi-medicated Sirt7 knockdown resulted in a significant inhibition of HAoSMCs proliferation following serum or Platelet-derived growth factor BB (PDGF-BB) stimulation as determined by cell count, BrdU cell proliferation assay and MTS proliferation assay. Knockdown of endogenous Sirt7 also reduced cell migration as revealed by Boyden chamber migration assay. The Cyclin D1 and Cyclin dependent kinase 2 (CDK2) protein levels were significantly decreased in Sirt7 siRNA-treated HAoSMCs in response to serum or PDGF-BB stimulation. In endothelial cells, knockdown of Sirt7 attenuated tube formation, proliferation and migration. These changes were accompanied by reduced ERK activation and VCAM-1 mRNA and protein expression in Sirt7 siRNA-treated HUVECs. Conversely, overexpression of Sirt7 by adenovirus enhanced tube formation and cell proliferation. In vivo, blood flow recovery in response to hindlimb ischemia was significantly attenuated in Sirt7-/- mice compared with WT mice. There was no difference in blood flow recovery between WT mice transplanted with WT or Sirt7-/- BM cells suggesting that Sirt7 deficiency in vascular cells have a predominant effect on attenuated blood flow recovery in response to hindlimb ischemia.
Conclusions: Sirt7 in blood vessel components have an important role in maintenance of vascular function. Sirt7 could be a promising therapeutic target for vascular diseases.
Author Disclosures: Y. Kimura: None. Y. Izumiya: None. S. Araki: None. S. Yamamura: None. Y. Onoue: None. S. Hanatani: None. H. Ogawa: Other Research Support; Modest; Astellas Pharma Inc, Bristol-Myers Squibb Company, Chugai Pharmaceutical Co, Ltd., Dainippon Sumitomo Pharma Co., Ltd., MSD K.K., Mochida Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Otsuka, Pfizer Japan Inc, Takeda Pharmaceutical Co., Ltd.. Other Research Support; Significant; Bayer, Daiichi Sankyo Co., Ltd., Novartis Pharma K.K., Sanofi K.K.. Honoraria; Modest; AstraZeneca K.K., Boehringer Ingelheim Japan, Bristol-Myers Squibb Company, Mitsubishi Tanabe Pharma, Pfizer Japan Inc, Sanofi K.K., Teijin Pharma Co., Ltd. Honoraria; Significant; Bayer Yakuhin, Ltd., Daiichi Sankyo Co., Ltd., MSD K.K., Takeda Pharmaceutical Co., Ltd..
- © 2015 by American Heart Association, Inc.