Understanding the involvement of mitochondrial inner membrane hyperpolarization in the development of myointimal hyperplasia
Final Report Abstract
Cardiovascular disease is the predominant cause of human morbidity and mortality in developed countries. Thus, extraordinary effort has been devoted to determine the molecular and pathophysiological characteristics of the diseased vasculature with the goal of developing novel diagnostic and therapeutic strategies to treat associated diseases (such as coronary artery disease or peripheral artery disease). Vessel injury triggers proliferative activity in vascular smooth muscle cells (SMCs) and concurrently suppresses their ability to undergo apoptosis. This temporary imbalance between SMC amplification and death leads to a largely positive net increase in cellularity, leading to myointimal hyperplasia. Activation of pyruvate dehydrogenase (PDH) via inhibition of its endogenous inhibitor PDK2, prevents the induction of apoptosis resistance in SMCs, maintains the homeostatic growth balance, and prevents vessel narrowing. This study aimed to reveal the mechanism of this very effective and novel treatment and to screen for alternative drug candidates for translational use. We could show that SMC mO2- is suppressed in chronically PDGF-stimulated SMCs and in the developing myointima of balloon-injured arteries, allowing SMCs to acquire resistance to apoptosis. In pyruvate dehydrogenase kinase-2 (Pdk2)-knockout mice, mO2- was maintained after balloon injury and mice showed mitigated myointima formation. Pharmacologic Pdk2 inhibition also prevented mO2- suppression and reduced restenosis. In Sm22-Cre×mCat mice that carry an SMC-specific mitochondrially tagged form of catalase, mO2- was constantly depleted and those mice showed strong myointima formation. Mechanistically we could show that mO2- facilitates SMC apoptosis, restores the growth balance, maintains the contractile SMC phenotype, and prevents de-differentiation. Five cancer drugs that increase mO2- were shown to significantly reduce myointima formation but their anti-restenotic potency was alleviated when combined with a potent ROS scavenger. mO2-, however, did affect the progression of atherosclerosis in Apolipoprotein E deficient (ApoE-/-) mice. We thus conclude that mO2- is a major regulator of restenosis but not atherosclerosis. Agents that enhance mO2- may be beneficial in the immediate post-balloon dilatation period during which SMCs have deranged mO2- homeostasis.
