Valsartan attenuates pulmonary hypertension via suppression of mitogen activated protein kinase signaling and matrix metalloproteinase expression in rodents.

Abstract

It has previously been demonstrated that the renin-angiotensin system is involved in the pathogenesis and development of pulmonary hypertension (PH). However, the efficacy of angiotensin II type I (AT1) receptor blockers in the treatment of PH is variable. The present study examined the effects of the AT1 receptor blocker valsartan on monocrotaline (MCT)‑induced PH in rats and chronic hypoxia‑induced PH in mice. The results demonstrated that valsartan markedly attenuated development of PH in rats and mice, as indicated by reduced right ventricular systolic pressure, diminished lung vascular remodeling and decreased right ventricular hypertrophy, compared with vehicle treated animals. Immunohistochemical analyses of proliferating cell nuclear antigen expression revealed that valsartan suppressed smooth muscle cell proliferation. Western blot analysis demonstrated that valsartan limited activation of p38, c‑Jun N‑terminal kinase 1/2 and extracellular signal‑regulated kinase 1/2 signaling pathways and significantly reduced MCT‑induced upregulation of pulmonary matrix metalloproteinases‑2 and ‑9, and transforming growth factor‑β1 expression. The results suggested that valsartan attenuates development of PH in rodents by reducing expression of extracellular matrix remodeling factors and limiting smooth muscle cell proliferation to decrease pathological vascular remodeling. Therefore, valsartan may be a valuable future therapeutic approach for the treatment of PH.

• Authors: Yuyan Lu, Haipeng Guo, Yuxi Sun, Xin Pan, Jia Dong, Di Gao, Wei Chen, Yawei Xu, Dachun Xu
• Journal: Molecular medicine reports (Mol Med Rep) Vol. 16 Issue 2 Pg. 1360-1368 (Aug 2017) ISSN: 1791-3004 [Electronic] Greece
• PMID: 28586065 (Publication Type: Journal Article)

Chemical References

• Transforming Growth Factor beta1
• Monocrotaline
• Valsartan
• Mitogen-Activated Protein Kinases
• Matrix Metalloproteinases

Topics

• Animals
• Blood Pressure (drug effects)
• Cell Proliferation (drug effects)
• Extracellular Matrix (drug effects, metabolism)
• Fibrosis
• Hypertension, Pulmonary (complications, drug therapy, enzymology, physiopathology)
• Hypertrophy, Right Ventricular (complications, drug therapy, pathology, physiopathology)
• Lung (pathology)
• MAP Kinase Signaling System (drug effects)
• Male
• Matrix Metalloproteinases (metabolism)
• Mice, Inbred C57BL
• Mitogen-Activated Protein Kinases (metabolism)
• Monocrotaline
• Phosphorylation (drug effects)
• Rats, Sprague-Dawley
• Systole (drug effects)
• Transforming Growth Factor beta1 (metabolism)
• Valsartan (pharmacology, therapeutic use)
• Vascular Remodeling (drug effects)