TY - JOUR
T1 - Locally applied leptin induces regional aortic wall degeneration preceding aneurysm formation in apolipoprotein E-deficient mice
AU - Tao, Ming
AU - Yu, Peng
AU - Nguyen, Binh T.
AU - Mizrahi, Boaz
AU - Savion, Naphtali
AU - Kolodgie, Frank D.
AU - Virmani, Renu
AU - Hao, Shuai
AU - Ozaki, C. Keith
AU - Schneiderman, Jacob
PY - 2013/2
Y1 - 2013/2
N2 - Objective-: Leptin promotes atherosclerosis and vessel wall remodeling. As abdominal aortic aneurysm (AAA) formation involves tissue remodeling, we hypothesized that local leptin synthesis initiates and promotes this process. METHODS AND RESULTS-: Human surgical AAA walls were analyzed for antigen and mRNA levels of leptin and leptin receptor, as well as mRNA for matrix metalloproteinases (MMP)-9 and MMP-12. Leptin and leptin receptor antigen were evident in all AAAs, and leptin, MMP-9, and MMP-12 mRNA was increased relative to age-matched nondilated controls. To simulate in vivo local leptin synthesis, ApoE mice were subjected to a paravisceral periaortic application of low-dose leptin. Leptin-treated aortas exhibited decreased transforming growth factor-β and increased MMP-9 mRNA levels 5 days after surgery, and leptin receptor mRNA was upregulated by day 28. Serial ultrasonography demonstrated accelerated regional aortic diameter growth after 28 days, correlating with local medial degeneration, increased MMP-9, MMP-12, and periadventitial macrophage clustering. Furthermore, the combination of local periaortic leptin and systemic angiotensin II administration augmented medial MMP-9 synthesis and aortic aneurysm size. CONCLUSION-: Leptin is locally synthesized in human AAA wall. Paravisceral aortic leptin in ApoE mice induces local medial degeneration and augments angiotensin II-induced AAA, thus suggesting novel mechanistic links between leptin and AAA formation.
AB - Objective-: Leptin promotes atherosclerosis and vessel wall remodeling. As abdominal aortic aneurysm (AAA) formation involves tissue remodeling, we hypothesized that local leptin synthesis initiates and promotes this process. METHODS AND RESULTS-: Human surgical AAA walls were analyzed for antigen and mRNA levels of leptin and leptin receptor, as well as mRNA for matrix metalloproteinases (MMP)-9 and MMP-12. Leptin and leptin receptor antigen were evident in all AAAs, and leptin, MMP-9, and MMP-12 mRNA was increased relative to age-matched nondilated controls. To simulate in vivo local leptin synthesis, ApoE mice were subjected to a paravisceral periaortic application of low-dose leptin. Leptin-treated aortas exhibited decreased transforming growth factor-β and increased MMP-9 mRNA levels 5 days after surgery, and leptin receptor mRNA was upregulated by day 28. Serial ultrasonography demonstrated accelerated regional aortic diameter growth after 28 days, correlating with local medial degeneration, increased MMP-9, MMP-12, and periadventitial macrophage clustering. Furthermore, the combination of local periaortic leptin and systemic angiotensin II administration augmented medial MMP-9 synthesis and aortic aneurysm size. CONCLUSION-: Leptin is locally synthesized in human AAA wall. Paravisceral aortic leptin in ApoE mice induces local medial degeneration and augments angiotensin II-induced AAA, thus suggesting novel mechanistic links between leptin and AAA formation.
KW - abdominal aortic aneurysm
KW - angiotensin II
KW - leptin
KW - transforming growth factor-β
KW - vessel wall remodeling
UR - http://www.scopus.com/inward/record.url?scp=84872959139&partnerID=8YFLogxK
U2 - 10.1161/ATVBAHA.112.300543
DO - 10.1161/ATVBAHA.112.300543
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C2 - 23220275
AN - SCOPUS:84872959139
SN - 1079-5642
VL - 33
SP - 311
EP - 320
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 2
ER -