Cigarette smoke–induced MMP2 and MMP9 secretion from aortic vascular smooth cells is mediated via the Jak/Stat pathway

• Published in: Human pathology 2015-02, Vol.46 (2), p.284-294
• Main Authors: Ghosh, Abhijit, PhD, Pechota, Angela, LVT, Coleman, Dawn, MD, Upchurch, Gilbert R., MD, Eliason, Jonathan L., MD
• Format: Article
• Language: English
• Subjects: Abdominal aortic aneurysm; Animals; Aorta - metabolism; Cells, Cultured; Cigarette smoke; Cigarettes; Disease; Humans; Jak2; Janus Kinase 2 - metabolism; Male; Matrix metalloproteinase; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - metabolism; Myocytes, Smooth Muscle - metabolism; Pathology; Proteins; Rats; Signal Transduction - physiology; Smoking - adverse effects; Smooth muscle; Stat3; STAT3 Transcription Factor - metabolism; Studies; Transcription factors
• ISSN: 0046-8177; 1532-8392
• DOI: 10.1016/j.humpath.2014.11.003

Summary It is hypothesized that cigarette smoke may increase MMP2 and MMP9 secretion through Jak/Stat pathway in the aorta, thereby facilitating abdominal aortic aneurysm (AAA) formation/progression in smokers. We observed through zymograms that treatment of male rat aortic vascular smooth muscle cells (RASMC) with an aqueous extract of cigarette smoke (CSE) for 24 hours resulted in a significant increase in pro-MMP9 ( P = .005) and a modest increase in pro-MMP2 ( P = .055) production. Western blot with protein extracts from CSE-treated RASMC showed up-regulation of pStat3, pJak2, and T-Jak2 and unchanged levels of T-Stat3. Transfection of RASMC with small interfering RNAs for Jak2, Stat3, or both Jak2 and Stat3 significantly reduced pro-MMP9 ( P < .005) and pro-MMP2 ( P < .05) in medium of CSE-treated RASMC compared with control small interfering RNA–transfected cells. Immunoprecipitation with total Jak2 antibody showed increased pStat3 and T-Stat3 in the cytoplasm and nucleus of CSE-treated RASMC. Immunofluorescence revealed increased presence of pJak2, T-Jak2, pStat3, and T-Stat3 in the cytoplasm and nucleus of the CSE-treated cells. Treatment of control human tissues with CSE resulted in pro-MMP9 secretion and up-regulation of the Jak/Stat proteins. In addition, AAA tissues showed more pJak2 and pStat3 than control human tissues. Therefore, inhibiting the Jak/Stat pathway could be a potential therapeutic approach in the treatment of AAA.