Inhibition of Epac1 suppresses mitochondrial fission and reduces neointima formation induced by vascular injury.
Vascular smooth muscle cell (VSMC) activation in response to injury plays an important role in the development of vascular proliferative diseases, including restenosis and atherosclerosis. The aims of this study were to ascertain the physiological functions of exchange proteins directly activated by cAMP isoform 1 (Epac1) in VSMC and to evaluate the potential of Epac1 as therapeutic targets for neointima formation during vascular remodeling. In a mouse carotid artery ligation model, genetic knockdown of the Epac1 gene led to a significant reduction in neointima obstruction in response to vascular injury. Pharmacologic inhibition of Epac1 with an Epac specific inhibitor, ESI-09, phenocopied the effects of Epac1 null by suppressing neointima formation and proliferative VSMC accumulation in neointima area. Mechanistically, Epac1 deficient VSMCs exhibited lower level of PI3K/AKT signaling and dampened response to PDGF-induced mitochondrial fission and reactive oxygen species levels. Our studies indicate that Epac1 plays important roles in promoting VSMC proliferation and phenotypic switch in response to vascular injury, therefore, representing a therapeutic target for vascular proliferative diseases.
Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center, Houston, Texas, USA.|Texas Therapeutics Institute, The University of Texas Health Science Center, Houston, Texas, USA.|The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas, USA.
Hui
H
Wang
Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center, Houston, Texas, USA.|Texas Therapeutics Institute, The University of Texas Health Science Center, Houston, Texas, USA.|The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas, USA.
William G
WG
Robichaux
Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center, Houston, Texas, USA.
Ziqing
Z
Wang
Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center, Houston, Texas, USA.|Texas Therapeutics Institute, The University of Texas Health Science Center, Houston, Texas, USA.|The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas, USA.
Fang C
FC
Mei
Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center, Houston, Texas, USA.|Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
Ming
M
Cai
Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center, Houston, Texas, USA.
Guangwei
G
Du
Department of Medicine, University of California, San Diego, La Jolla, California, USA.
Ju
J
Chen
Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center, Houston, Texas, USA.|Texas Therapeutics Institute, The University of Texas Health Science Center, Houston, Texas, USA.|The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas, USA.
Xiaodong
X
Cheng
D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism* / Q000473:pathology; D020212:Carotid Artery Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006835:Hydrazones / Q000494:pharmacology*; D007555:Isoxazoles / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D063154:Mitochondrial Dynamics / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D058426:Neointima / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
C579558:3-(5-tert-butylisoxazol-3-yl)-2-((3-chlorophenyl)hydrazono)-3-oxopropionitrile; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D006835:Hydrazones; D007555:Isoxazoles