TRPM7 channels as novel target for cardiovascular disorders

Inoue, Koichi

Abstract

The long-term goal of this project is to explore the potential that Transient receptor potential melastatin 7 (TRPM7) channels are novel therapeutic targets for cardiovascular disorders. Although TRPM7 channels have been shown to play a role in ischemic brain injury and in cancer development, it is largely unknown whether they play an important role in normal function and injury of cardiovascular systems. We hypothesize that endothelial TRPM7 channels play critical roles in regulating vascular functions under physiological and pathophysiological conditions. This hypothesis is based on the following preliminary data: 1) Silencing TRPM7 channels promotes growth/proliferation of human umbilical endothelial cells (HUVECs) and nitric oxide (NO) production; 2) Silencing TRPM7 enhances HUVEC migration and tube formation, key in vitro evidence for angiogenesis; 3) treatment of vascular endothelial cells with high glucose, at the concentration relevant to diabetes, facilitates TRPM7 expression and increases oxidative stress; 4) expression of TRPM7 is enhanced in vascular tissues of diabetic mice. To test our hypothesis, the following specific aims will be examined:
Aims 1 : to determine the effect of TRPM7 knockdown on migration and angiogenic activities of vascular endothelial cells.
Aims 2 : to determine the molecular mechanism underlying the effect of TRPM7 on vascular endothelial cells.
Aims 3 : to investigate the role of TRPM7 in the injury of vascular endothelial cells under hyperglycemic conditions Aim 4: to investigate the role of TRPM7 in vascular endothelial functions under diabetic condition in vivo.

Public Health Relevance

The detailed roles of TRPM7 channels in regulating the functions of vascular endothelial cells and its implication in cardiovascular disorders in vivo remained to be determined. This study will address the contribution of TRPM7 to vascular endothelial function both in vitro and in vivo under physiological and pathophysiological conditions.