The Role of Age-Rage System in Monocytes and Its Involvement in Diabetic Vascular Complication

Atherosclerosis and its complications constitute the most common causes of death in Western societies and Japan. As our people's dietary habits become more westernized and the incidence of diabetes in Taiwan remains at high level, the diabetes-related cardiovascular diseases appear to more significantly threaten our health and life. Although the potential mechanism of how diabetes accelerate atherosclerosis has been studied for many years, investigations focused on the role of monocytes in this process are actually very limited. Increasing evidence suggests a more important role of monocyte-macrophage in diabetic vascular complication. In this proposal, we aim to investigate how advanced glycation end products and its receptors regulate the monocyte recruitment both in vitro and in vivo. Mechanism underlying the potential anti-atherosclerotic effect of berberine will also be studied. Specific Aims 1st year To investigate the underlying mechanisms for the AGEs-induced monocyte adhesion to endothelial cells. To investigate the underlying mechanisms for the AGEs-induced migration of monocytes toward chemokines. To study the inhibitory effects of berberine on the AGEs-induced recruitment of monocytes and its related molecular mechanism. 2nd year To investigate the regulatory mechanism of RAGE functional expression in monocyts by TNF-α or angiotensin II To study the effect of TNF-α or angiotensin II on the transcriptional control of RAGE gene in monocytes by transcription activity analysis and gel retardation assay The effects of AGEs on enhancing the adhesion and migration of monocytes will be further examined in TNF--α or angiotensin II-treated monocytes 3rd year To investigate the in vivo monocyte recruitment and activities in diabetic rat models To examine the effect of berberine on the in vivo vascular monocyte recruitment and ex vivo monocyte activities in the diabetic rat model and compare with the effect of pioglitazone.

Project ID:PC9709-0935
External Project ID:NSC97-2320-B182-019