Genetic Deletion of Socs3 in Smooth Muscle Cells Ameliorates Aortic Dissection in Mice

Objective—We aimed to elucidate how the inflammatory response is involved in AD progression and the associated tissue destruction, focusing on the role of Jak/Stat signaling in smooth muscle cells (SMCs). Background—Aortic dissection (AD) is caused by disruption of the intima-media complex and tearing of the medial layer of the aorta. AD is life-threatening due to progressive destruction of the aorta, resulting in critical damage to organs. Recent studies reveal that the inflammatory response, including Jak/Stat signaling, is important in AD pathogenesis. However, it remains unclear how Jak/Stat signaling is involved in the tissue destruction in AD. Methods—Immunohistochemical analysis of human AD tissue revealed activation of signal transducer and activator of transcription 3 (Stat3) in medial SMCs. Stat3 activation was recapitulated in a mouse model of AD induced via β-aminopropionitrile and angiotensin II infusion. We also created a knockout mouse strain (smSocs3-KO) by deleting Socs3, a negative regulator of Jak/Stat signaling, specifically in mouse SMCs. Results—Compared to wild-type mice, smSocs3-KO mice developed a less severe AD phenotype that was associated with proinflammatory response at baseline, increased fibroblast and collagen deposition, and reinforced aortic tensile strength. Cell culture experiments revealed that Stat3 activation in SMCs caused secretion of factors that can stimulate fibroblast growth. Conclusions—Our present findings suggested that, although an acute inflammatory response is detrimental in AD, chronic activation of the SMC-mediated proinflammatory response was protective against aortic destruction in AD. To achieve the smooth muscle-specific deletion of Socs3 (smSocs3-KO), we crossed mice that were homozygous for the floxed allele of Socs3 (Socs3fl/fl) and backcrossed to C57BL/6J for three generations, with SM22-Cre mice (JAX Mice, stock # 004746) that carried a Cre recombinase transgene under control of the smooth muscle SM22 promoter. Socs3fl/fl littermate mice lacking the SM22-Cre transgene served as wild type (WT) controls. As a mouse model of aortic dissection, BAPN (150 mg/kg/day) and angiotensin II (AngII; 1000 ng/kg/min) were simultaneously administered to mice with (smSocs3-KO) or without (WT) SM22-Cre transgene using osmotic minipumps (Alzet model 1002). Aortic samples were obtained with or without 3 days of BAPN+AngII infusion.