Vascular calcification: Molecular mechanisms and therapeutic interventions

Abstract

Vascular calcification (VC) is recognized as a pathological vascular disorder associated with various diseases, such as atherosclerosis, hypertension, aortic valve stenosis, coronary artery disease, diabetes mellitus, as well as chronic kidney disease. Therefore, it is a life-threatening state for human health. There were several studies targeting mechanisms of VC that revealed the importance of vascular smooth muscle cells transdifferentiating, phosphorous and calcium milieu, as well as matrix vesicles on the progress of VC. However, the underlying molecular mechanisms of VC need to be elucidated. Though there is no acknowledged effective therapeutic strategy to reverse or cure VC clinically, recent evidence has proved that VC is not a passive irreversible comorbidity but an active process regulated by many factors. Some available approaches targeting the underlying molecular mechanism provide promising prospects for the therapy of VC. This review aims to summarize the novel findings on molecular mechanisms and therapeutic interventions of VC, including the role of inflammatory responses, endoplasmic reticulum stress, mitochondrial dysfunction, iron homeostasis, metabolic imbalance, and some related signaling pathways on VC progression. We also conclude some recent studies on controversial interventions in the clinical practice of VC, such as calcium channel blockers, renin-angiotensin system inhibitions, statins, bisphosphonates, denosumab, vitamins, and ion conditioning agents.

Keywords: endoplasmic reticulum stress; mitochondrial dysfunction; molecular mechanism; therapeutic interventions; vascular calcification.

FIGURE 1

Multiple diseases related to vascular calcification (VC). VC participate in a lot of pathological process of several chronic diseases, such as cerebrovascular diseases, peripheral arteria diseases, and coronary artery disease (CAD)

FIGURE 2

Influence of endoplasmic reticulum stress (ERS) on vascular calcification. Protein kinase RNA‐like endoplasmic reticulum kinase (PERK), inositol‐requiring enzyme 1 (IRE1), activating transcription factor‐6 (ATF6), and caspase signaling pathway promote vascular calcification (VC) by mediating unfolded protein response (UPR). Under unstressed circumstance by which PERK, IRE1, and ATF6 are combined with Grp78/BIP in inactive state. During pathological stimulation or unfolded/misfolded proteins accumulate in the endoplasmic reticulum (ER) luminal, the ER resident protein separate from these transmembrane protein sensors and further activate the UPR. Activated PERK phosphorylates eIF1α and promotes the protein translation. Reversely, ATF4 expression is increased. Phosphorylated IRE1 promotes the splice of X‐box binding protein 1 (XBP1) mRNA, leading to the XBP1 production. In addition, separated ATF6 is translated into the Golgi apparatus where it is cleaved by the proteolysis. Cleaved ATF6 subsequently moves into the nucleus and springs for the transcription of ER chaperones as well. Finally, caspase‐12 is activated by ERS. Functional caspase‐12 directly activates caspase‐9, which activates caspase‐3 in turn and eventually leads to apoptosis. These respective downstream processes of the four sensors accelerate VC of vascular smooth muscle cells (VSMCs)

FIGURE 3

Mitochondrial dysfunction plays a key role in the progression of vascular calcification (VC). Oxidative stress, apoptosis, excessive fission, and rare mitophagy have been reported to damage the normal structure of mitochondria and impair respiratory function, resulting in the transformation of vascular smooth muscle cells (VSMCs) from contractile to osteoblast‐like cells and, therefore, VC‐mediated

FIGURE 4

Ferroptosis can be initiated by many factors to induce vascular calcification (VC). Mitochondria dysfunction, endoplasmic reticulum stress (ERS), inflammation, and iron homeostasis promote ferroptosis by initiating factor for inflammation or pro‐inflammatory effects, which contributes to vascular calcification