Defective Protein Catabolism in Atherosclerotic Vascular Inflammation

Abstract

Vascular inflammation in atheroprone vessels propagates throughout the arterial tree in dyslipidemic patients, thereby accelerating atherosclerotic progression. To elucidate the mechanism of vascular inflammation, most previous studies have focused on inflammation-related signals that are sent in response to vasoactive stimuli. However, it is also important to understand how normal blood vessels become defective and start degenerating. Growing evidence suggests that major protein catabolism pathways, including the ubiquitin-proteasome, autophagy, and calpain systems, are disturbed in atheroprone vessels and contribute to the pathogenesis of atherosclerosis. Indeed, dysregulation of ubiquitin–proteasome pathways results in the accumulation of defective proteins in blood vessels, leading to vascular endothelial dysfunction and apoptosis in affected cells. Impaired autophagy-lysosomal degradation affects smooth muscle cell transformation and proliferation, as well as endothelial integrity and phagocytic clearance of cellular corpses. Dysregulation of the calpain system confers proatherogenic properties to endothelial cells, smooth muscle cells, and macrophages. In this review article, we will discuss the current information available on defective protein catabolism in atheroprone vessels and its potential interrelation with inflammation-related signals.

Endothelial calpain systems orchestrate myofibroblast differentiation during wound healing

“…Calpain systems are posttranscriptional cell regulation systems (11)(12)(13) that reportedly mediate dermal wound healing (10). They are potentiated by extracellular stressors (e.g., growth factors, hypoxia, mechanical stress), by modulating cellular processes (cell motility), and by inflammatory cascades (11)(12)(13). Our previous study showed that calpain overactivation triggered by the loss of calpastatin potentiates inflammatory signaling in ECs, thereby accelerating cytokine-driven angiogenesis (16).…”

“…Recent studies have reported a role for calpain proteolytic systems in dermal wound healing (10). Calpains are calcium-dependent intracellular proteases that are activated by exogenous stressors such as physical stress, as well as by cytokines, growth factors, and hypoxia (11)(12)(13). In vascular endothelial cells (ECs), calpain systems are associated with sprouting angiogenesis (14,15).…”

Plasma MicroRNA-29c Levels Are Associated with Carotid Intima-Media Thickness and is a Potential Biomarker for the Early Detection of Atherosclerosis

“…We found that miR-29c levels were higher in patients with increased CIMT than in those with normal CIMT values. At the same time, vascular inflammation in atheroprone vessels propagates throughout the arterial tree in dyslipidemic patients, thereby accelerating atherosclerotic progression [27]. CRP is one of the most commonly used biomarkers for inflammation in clinical practices.…”

Calpain proteolytic systems counteract endothelial cell adaptation to inflammatory environments

“…Moreover, dysregulation of the ubiquitin-proteasome system can contribute to atherogenesis [10], defective angiogenesis [11], and insufficient production of vasomodulatory substances such as endothelin and nitric oxide [12]. In addition to autophagy and proteasomal function, calpain proteolytic systems have been shown to play a role in vascular regulation [13][14][15]. In this review, we summarize our current understanding of calpainassociated regulation of EC functions under inflammatory and non-inflammatory conditions, and we discuss the contribution of aberrant intracellular proteolysis to defective adaptation of ECs to the inflammatory environment.…”