IKCal Up-Regulation Mediates Atherosclerosis

Project Description Narrative:

Vascular smooth muscle cell (VSMC) proliferation and migration play a crucial role in the intimal and medial thickening in atherosclerosis. The de-differentiation and conversion from contractile to proliferative phenotype lead to their multiplication. Proliferative VSMCs predominantly express intermediate conductance calcium-activated K+ channels (IKCa), while the contractile phenotype possesses large conductance KCa. This differential KCa expression is closely related to the growth of VSMCs. The researchers hypothesize that VSMC IKCa up-regulation mediates in the development of atherosclerosis.

They will test this hypothesis in three ways. First, they will determine if IKCa is up-regulated in mitogen-stimulated VSMCs and in VSMCs from mice and humans with atherosclerosis. Second, they will test the hypothesis that IKCa up-regulation is required for DNA synthesis and cell cycle progression in VSMCs by regulating intracellular calcium levels. Third, the role of IKCa in the development of atherosclerosis will be determined by studying the effects of pharmacological blockade or knockdown of IKCa on atherosclerotic formation in mice. Collectively, these aims address a novel mechanistic approach to the development of atherosclerosis by examining the role of IKCa activity in the vascular remodeling. These studies could open new strategies for the prevention and/or treatment of atherosclerosis.