title: Inhibition of leptin-induced vascular extracellular matrix remodelling by adiponectin.
abstract: Vascular extracellular matrix (ECM) remodelling, which is the result of disruption in the balance of ECM synthesis and degradation, induces vessel fibrosis and thereby leads to hypertension. Leptin is known to promote tissue fibrosis, while adiponectin has recently been demonstrated to be anti-fibrogenic in tissue fibrosis. In this study, we aimed to evaluate the leptin-antagonist function of adiponectin and to further elucidate the mechanisms through which adiponectin dampens leptin signalling in vascular smooth muscle cells, thus preventing excess ECM production, in our already established 3D co-culture vessel models. Our 3D co-culture vessel model, which mimics true blood vessels, is composed of vascular endothelial cells, vascular smooth muscle cells and collagen type I. We validated the profibrogenic effects of leptin and analysed matrix metalloproteinase 2 (MMP2), MMP9, tissue inhibitor of metalloproteinase 1 (TIMP1) and collagen types II/IV secretion in 3D vessel models. The protective/inhibitory effects of adiponectin were re-analysed by inhibiting adiponectin receptor 1 (AdipoR) and AdipoR2 expression in endothelial cells using RNAi technology. In the 3D vessel models, adiponectin blocked the leptin-stimulated secretion of collagen types II/IV and TIMP1 while significantly increasing MMP2/9 activity. In endothelial cells, adiponectin induced phosphorylation of AMPK, thereby suppressing leptin-mediated STAT3 phosphorylation through induction of SOCS3 in smooth muscle cells. Our findings indicate that adiponectin disrupted the leptin-induced vascular ECM remodelling via AdipoR1 and enhanced AMPK signalling in endothelial cells, which, in turn, promoted SOCS3 up-regulation in smooth muscle cells to repress leptin-stimulated phosphorylation of STAT3.
authors: Department of CardiologySchool of Medicine, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, People's Republic of ChinaDepartment of CardiologyHuai'an First People's Hospital, Nanjing Medical University, Jiangsu Province 223300, People's Republic of China.
authors: Zhi
authors: Z
authors: Zhang
authors: Department of CardiologySchool of Medicine, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, People's Republic of ChinaDepartment of CardiologyHuai'an First People's Hospital, Nanjing Medical University, Jiangsu Province 223300, People's Republic of China.
authors: Fang
authors: F
authors: Wang
authors: Department of CardiologySchool of Medicine, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, People's Republic of ChinaDepartment of CardiologyHuai'an First People's Hospital, Nanjing Medical University, Jiangsu Province 223300, People's Republic of China.
authors: Bing-Jian
authors: BJ
authors: Wang
authors: Department of CardiologySchool of Medicine, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, People's Republic of ChinaDepartment of CardiologyHuai'an First People's Hospital, Nanjing Medical University, Jiangsu Province 223300, People's Republic of China.
authors: Guang
authors: G
authors: Chu
authors: Department of CardiologySchool of Medicine, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, People's Republic of ChinaDepartment of CardiologyHuai'an First People's Hospital, Nanjing Medical University, Jiangsu Province 223300, People's Republic of China.
authors: Qunan
authors: Q
authors: Cao
authors: Department of CardiologySchool of Medicine, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, People's Republic of ChinaDepartment of CardiologyHuai'an First People's Hospital, Nanjing Medical University, Jiangsu Province 223300, People's Republic of China.
authors: Bao-Gui
authors: BG
authors: Sun
authors: Department of CardiologySchool of Medicine, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, People's Republic of ChinaDepartment of CardiologyHuai'an First People's Hospital, Nanjing Medical University, Jiangsu Province 223300, People's Republic of China daiqiuyan@medmail.com.cn.
authors: Qiu-Yan
authors: QY
authors: Dai
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism; D018929:Cell Culture Techniques; D024043:Collagen Type II / Q000378:metabolism; D024141:Collagen Type IV / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D020868:Gene Silencing; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D020738:Leptin / Q000378:metabolism* / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D054419:Receptors, Adiponectin / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
chemical_list: C475418:ADIPOR1 protein, human; C475420:ADIPOR2 protein, human; D052242:Adiponectin; D024043:Collagen Type II; D024141:Collagen Type IV; D020738:Leptin; D054419:Receptors, Adiponectin; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D055372:AMP-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: 3D vessel model; adiponectin; extracellular matrix remodelling; hypertension; leptin; obesity