Small GTP-binding proteins and mitogen-activated protein kinases as promising therapeutic targets of vascular remodeling.
OBJECTIVE
To summarize the most recent findings concerning the targeting of mitogen-activated protein kinases and small GTP-binding proteins toward vascular remodeling together with molecular mechanisms of their activations in vascular pathophysiology.


RESULTS
In addition to targeting the classical Ras/extracellular signal-regulated kinase cascade, Rho-kinase inhibitors, as well as the HMG-CoA reductase inhibitors, or 'statins', have pleiotropic efficacy for experimental cardiovascular diseases that involve inhibition of the signal transduction cascades originated by the small GTP-binding proteins such as Rho and Rac. Moreover, the underlying molecular mechanisms of the activation of these small GTP-binding proteins and downstream mitogen-activated protein kinases in cardiovascular tissue and cells have recently been better characterized. Additionally, gene-targeting studies in animal models are revealing select roles of the isoforms of these signaling proteins in the pathophysiology of cardiovascular disease. This is exemplified by the role of c-Jun NH(2)-terminal kinases in mediating atherosclerosis and diabetes.


CONCLUSIONS
Characterization of the function of small GTP-binding proteins, mitogen-activated protein kinases and their effectors in cardiovascular pathophysiology can be readily identified by using select inhibitors, dominant-negative gene transfer and the generation of select gene-targeted animals. These findings strongly support the notion that small GTP-binding proteins and mitogen-activated protein kinases are promising therapeutic targets toward cardiovascular diseases.
Shirai
Heigoro
H
Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Autieri
Michael
M
Eguchi
Satoru
S
D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000502:physiology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014652:Vascular Diseases / Q000503:physiopathology* / Q000628:therapy; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins