Abstract
Vascular calcification (VC) describes the pathophysiological phenotype of calcium apatite deposition within the vascular wall, leading to vascular stiffening and the loss of compliance. VC is never benign; the presence and severity of VC correlate closely with the risk of myocardial events and cardiovascular mortality in multiple at-risk populations such as patients with diabetes and chronic kidney disease. Mitochondrial dysfunction involving each of vascular wall constituents (endothelia and vascular smooth muscle cells (VSMCs)) aggravates various vascular pathologies, including atherosclerosis and VC. However, few studies address the pathogenic role of mitochondrial dysfunction during the course of VC, and mitochondrial reactive oxygen species (ROS) seem to lie in the pathophysiologic epicenter. Superoxide dismutase 2 (SOD2), through its preferential localization to the mitochondria, stands at the forefront against mitochondrial ROS in VSMCs and thus potentially modifies the probability of VC initiation or progression. In this review, we will provide a literature-based summary regarding the relationship between SOD2 and VC in the context of VSMCs. Apart from the conventional wisdom of attenuating mitochondrial ROS, SOD2 has been found to affect mitophagy and the formation of the autophagosome, suppress JAK/STAT as well as PI3K/Akt signaling, and retard vascular senescence, all of which underlie the beneficial influences on VC exerted by SOD2. More importantly, we outline the therapeutic potential of a novel SOD2-targeted strategy for the treatment of VC, including an ever-expanding list of pharmaceuticals and natural compounds. It is expected that VSMC SOD2 will become an important druggable target for treating VC in the future.
Highlights
Vascular calcification, the ectopic deposition of calcium apatite within the vascular wall, was previously thought to be a degenerative process predominantly involving individuals of advanced age
It is well established that vascular calcification affects those with diabetes mellitus (DM) and chronic kidney disease (CKD)/end-stage renal disease (ESRD) at an accelerated speed
We summarized available reports focusing on the upstream regulatory molecules of Superoxide dismutase 2 (SOD2) in vascular smooth muscle cells (VSMCs) in (Figure 1)
Summary
The ectopic deposition of calcium apatite within the vascular wall, was previously thought to be a degenerative process predominantly involving individuals of advanced age. The presence of vascular calcification confers detrimental cardiovascular influences through impairing vascular compliance and increasing stiffness, elevating systemic resistance and afterload, leading to cardiac hypertrophy, myocardial remodeling, and a greater risk of heart failure-related hospitalization [1]. The stiffened vessels beget a greater cardiac pulsatile force and rising luminal shear stress, which correlates with endothelial dysfunction and atherogenesis involving coronary and peripheral arteries [2]. Vascular calcification involving lower limbs is conducive to peripheral artery occlusion, causing intermittent claudication and compromised wound healing [1]. These findings lend support to the notion that vascular calcification is pathologically important and warrants a greater understanding of its pathophysiology
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