Published online before print July 5, 2007, doi: 10.1161/ATVBAHA.107.148353
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© 2007 American Heart Association, Inc.
Vascular Biology |
Leptin Induces C-Reactive Protein Expression in Vascular Endothelial Cells
From the Division of Cardiovascular Diseases, Department of Internal Medicine (P.S., M.H., R.W., A.S.M.S., V.K.S.), Mayo Clinic College of Medicine, Rochester, Minn; the Hypertension Unit (M.H.), Medical University of Gdansk, Poland; and Cardiovascular/Metabolic Diseases (R.W.), Pfizer Global Research & Development, Pfizer Inc, Groton, Conn.
Correspondence to Dr Virend K. Somers, MD, DPhil, Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic College of Medicine, 200 First Street, SW, Rochester, MN, 55905. E-mail somers.virend{at}mayo.edu
Objective— There is increasing evidence of an association between leptin and increased cardiovascular risk. Higher leptin levels are associated with increased levels of C-reactive protein (CRP), which itself elicits proatherogenic effects in the vascular endothelium. We tested the hypothesis that leptin induces CRP expression in human coronary artery endothelial cells (HCAECs).
Methods and Results— We confirmed the presence of both long and short isoforms of the leptin receptor in cultured HCAECs. Leptin but not IFN
A/D nor tumor necrosis factor (TNF) , induced expression of CRP. A dose dependent increase of CRP mRNA and protein was observed with increasing concentration of leptin (0 to 400 ng/mL). This increased CRP expression was attenuated in the presence of anti-leptin receptor antibodies and also by inhibition of ERK1/2 by PD98059 (20 to 40 µmol/L). Time (0 to 60 minutes) and leptin concentration (0 to 200 ng/mL)-dependence of ERK1/2 phosphorylation were evident in response to leptin treatment. Leptin also elicited ROS generation. Inhibition of ROS by catalase (200 µg/mL) prevented ERK1/2 phosphorylation and CRP mRNA transcription.
Conclusion— Leptin induces CRP expression in HCAECs via activation of the leptin receptor, increased ROS production, and phosphorylation of ERK1/2. These studies suggest a mechanism for the proatherogenic effects of leptin.
High leptin levels are associated with increased cardiovascular risk. In this study we provide evidence for leptin-dependent C-reactive protein (CRP) induction in vascular endothelial cells and investigated the signaling pathway involved. Thus, we demonstrate an additional molecular mechanism for the proatherogenic activity of leptin.
Key Words: leptin • endothelium • C-reactive protein • obesity • atherosclerosis
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