Cardioprotective effect of a combination of Rho-kinase inhibitor and p38 MAPK inhibitor on cardiovascular remodeling and oxidative stress in Dahl rats.

Abstract

AIM:

Rho-kinase plays a critical role in various cellular functions. p38 mitogen-activated protein kinase (p38 MAPK) plays a central role in the inflammatory cytokine response to immune challenge. We evaluated the effects of a combination of fasudil, a Rho-kinase inhibitor, and FR167653, a p38 MAPK inhibitor, on cardiovascular remodeling, inflammation, and oxidative stress in Dahl salt-sensitive hypertensive (DS) rats.

METHODS:

DS and Dahl salt-resistant (DR) rats were fed a high-salt diet at 6 weeks of age. Vehicle, fasudil (100 mg/kg per day), FR167653 (2 mg/kg per day), and a combination of fasudil and FR167653 were administered to 6-week-old DS rats for 5 weeks.

RESULTS:

At the age of 11 weeks, in the left ventricle, DS rats were characterized by increased myocardial fibrosis, phosphorylation of p38 MAPK, and myosin phosphatase targeting subunit (MYPT-1), and NAD(P)H oxidase p22(phox), p47(phox), gp91(phox), tumor necrosis factor-α and interleukin-1β expression compared with DR rats. Fasudil improved cardiovascular remodeling, inflammation, NAD(P)H oxidase subunits, and phosphorylation of p38 MAPK and MYPT-1. FR167653 also similarly ameliorated these indices but not MYPT-1 phosphorylation. Compared with either agent alone, a combination of fasudil and FR167653 was more effective for the improvement of myocardial damage, inflammation and oxidative stress.

CONCLUSION:

These findings suggest that the Rho-kinase and p38 MAPK pathways may play a pivotal role in ventricular hypertrophy; thus, we obtained the first evidence that a combination of Rho-kinase inhibitor and p38 MAPK inhibitor may provide a potential therapeutic target in hypertension with cardiovascular remodeling.

• Authors: Hiroshi Takeshima, Naohiko Kobayashi, Wataru Koguchi, Mayuko Ishikawa, Fumihiro Sugiyama, Toshihiko Ishimitsu
• Journal: Journal of atherosclerosis and thrombosis (J Atheroscler Thromb) Vol. 19 Issue 4 Pg. 326-36 ( 2012) ISSN: 1880-3873 [Electronic] Japan
• PMID: 22166971 (Publication Type: Journal Article)

Chemical References

• Cardiotonic Agents
• FR 167653
• Protein Kinase Inhibitors
• Pyrazoles
• Pyridines
• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
• rho-Associated Kinases
• p38 Mitogen-Activated Protein Kinases
• fasudil

Topics

• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine (analogs & derivatives, pharmacology)
• Animals
• Cardiotonic Agents (pharmacology)
• Male
• Oxidative Stress
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Pyrazoles (pharmacology)
• Pyridines (pharmacology)
• Rats
• Rats, Inbred Dahl
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• rho-Associated Kinases (antagonists & inhibitors, metabolism)