Small GTP-binding proteins and mitogen-activated protein kinases as promising therapeutic targets of vascular remodeling

Abstract

Purpose of review: 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.

Recent findings: 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.

Summary: 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.