Published ahead of print on August 27, 2004, doi:10.1164/rccm.200404-455OC Am. J. Respir. Crit. Care Med., Volume 170, Number 11, December 2004, 1204-1211 A more recent version of this article appeared on December 1, 2004
Submitted on April 3, 2004 C-Type Natriuretic Peptide Ameliorates Monocrotaline-induced Pulmonary Hypertension in RatsTakefumi Itoh1,1 Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, Suita, Osaka, Japan; Second Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan, 2 Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Internal Medicine, National Cardiovascular Center, Suita, Osaka, Japan, 3 Second Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan; Department of Internal Medicine, National Cardiovascular Center, Suita, Osaka, Japan, 4 Department of Cardiac Physiology, National Cardiovascular Center Research Institute, Suita, Osaka, Japan, 5 Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, Suita, Osaka, Japan, 6 Department of Pathology, National Cardiovascular Center, Suita, Osaka, Japan, 7 Department of Internal Medicine, National Cardiovascular Center, Suita, Osaka, Japan, 8 Second Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan, 9 Department of Biochemistry, National Cardiovascular Center Research Institute, Suita, Osaka, Japan * To whom correspondence should be addressed. E-mail: nagayann{at}hsp.ncvc.go.jp.
C-type natriuretic peptide has been shown to act as a local regulator of vascular tone and remodeling. We investigated whether C-type natriuretic peptide ameliorates monocrotaline-induced pulmonary hypertension in rats. Rats received continuous infusion of C-type natriuretic peptide or placebo. Significant pulmonary hypertension developed three weeks after monocrotaline. However, infusion of C-type natriuretic peptide significantly attenuated the development of pulmonary hypertension and vascular remodeling. Neither systemic arterial pressure nor heart rate was altered. Interestingly, C-type natriuretic peptide enhanced Ki-67 expression, a marker for cell proliferation, in pulmonary endothelial cells and augmented lung tissue content of endothelial nitric oxide synthase. C-type natriuretic peptide significantly suppressed apoptosis of pulmonary endothelial cells, decreased the number of monocytes/macrophages, and inhibited expression of plasminogen activator inhibitor type 1, a marker for fibrinolysis impairment, in the lung. In addition, C-type natriuretic peptide significantly increased the survival rate in monocrotaline rats. Finally, infusion of C-type natriuretic peptide after establishment of pulmonary hypertension also had beneficial effects on hemodynamics and survival. In conclusion, infusion of C-type natriuretic peptide ameliorated monocrotaline-induced pulmonary hypertension and improved survival. These beneficial effects may be mediated by regeneration of pulmonary endothelium, inhibition of endothelial cell apoptosis, and prevention of monocyte/macrophage infiltration and fibrinolysis impairment. Key words: natriuretic peptides, pulmonary hypertension, monocrotaline, vasoprotection
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