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Cardiovascular Research Advance Access originally published online on May 14, 2009
Cardiovascular Research 2009 83(4):768-777; doi:10.1093/cvr/cvp150
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Chlamydia heat shock protein 60 decreases expression of endothelial nitric oxide synthase in human and porcine coronary artery endothelial cells

Changyi Chen1,2,*, Hong Chai1, Xinwen Wang1, Peter H. Lin1,2 and Qizhi Yao1,2

1 Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery (R413), Molecular Surgeon Research Center, Baylor College of Medicine, One Baylor Plaza, Mail Stop: BCM390, Houston, TX 77030, USA
2 Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX 77030, USA

* Corresponding author. Tel: +1 713 798 4401; fax: +1 713 798 6633. E-mail address: jchen{at}bcm.tmc.edu

Aims: Clinically, Chlamydia pneumoniae infection and its heat shock protein 60 (cHSP60) may contribute to atherogenesis; however, its underlying mechanisms are largely unknown. The objective of this study was to determine whether cHSP60 could cause endothelial dysfunction in human coronary artery endothelial cells (HCAECs) and porcine coronary arteries.

Methods and results: When HCAECs were treated with recombinant cHSP60, endothelial nitric oxide synthase (eNOS) mRNA and protein levels, enzyme activities, cellular NO levels, mRNA stability, and promoter activities were significantly decreased. Superoxide anion production was significantly increased due to the inhibition of mitochondrial membrane potential and catalase and superoxide dismutase (SOD) activities as well as activation of NADPH oxidase. Antioxidant seleno-L-methionine (SeMet) or SOD mimetic MnTBAP effectively blocked cHSP60-induced eNOS downregulation. In addition, cHSP60 activated mitogen-activated protein kinases (MAPKs) including p38, c-Jun-N-terminal kinase/stress-activated protein kinase, and extracellular signal-regulated kinases. Specific chemical inhibitors or their dominant-negative mutant forms of these MAPKs effectively blocked cHSP60-induced eNOS downregulation. cHSP60-induced eNOS downregulation and oxidative stress were also demonstrated in porcine coronary artery rings in vitro. Functionally, endothelium-dependent vasorelaxation was significantly reduced in cHSP60-treated vessels.

Conclusion: cHSP60 directly induces eNOS downregulation through oxidative stress and MAPK activation in both HCAECs and porcine coronary arteries, thereby causing endothelial dysfunction.

KEYWORDS Chlamydia pneumonia; Heat shock protein 60; Endothelial nitric oxide synthase; Superoxide anion; MAPK; Oxidative stress; Antioxidant; SeMet; MnTBAP; Atherosclerosis

Time for primary review: 21 days


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