Key result
Calpain inhibition attenuates atherosclerosis and inflammation in mouse models.
Why the study?
Dysfunction of VE-cadherin-mediated adherence junctions in vascular endothelial cells is implicated in early atherosclerosis, but mechanisms of VE-cadherin disruption during atherogenesis are poorly understood.
Does calpain inhibition prevent VE-cadherin disorganization and atherosclerosis progression in preclinical models?
Does calpain inhibition prevent VE-cadherin disorganization and atherosclerosis progression in preclinical models?
Subtype-selective induction of m-calpain in aortic endothelial cells promotes atherosclerosis via VE-cadherin disorganization, suggesting m-calpain inhibition as a potential therapeutic strategy.
BACKGROUND: Although dysfunction of VE-cadherin-mediated adherence junctions in vascular endothelial cells (ECs) is thought to be one of the initial steps of atherosclerosis, little is known regarding how VE-cadherin is disrupted during atherogenic development. This study focused on the role of calpain, an intracellular cysteine protease, in the proteolytic disorganization of VE-cadherin and subsequent progression of atherosclerosis. METHODS AND RESULTS: Increased expression of m-calpain was observed in aortic ECs in atherosclerotic lesions in humans and low-density lipoprotein receptor-deficient (ldlr(-/-)) mice. Furthermore, proteolytic disorganization of VE-cadherin was shown in aortic ECs in ldlr(-/-) and apolipoprotein E-deficient (apoE(-/-)) mice. Long-term administration of calpain inhibitors into these mice attenuated atherosclerotic lesion development and proinflammatory responses, as well as VE-cadherin disorganization, without normalization of plasma lipid profiles. Furthermore, in vivo transfection of m-calpain siRNA to ldlr(-/-) mice prevented disorganization of VE-cadherin and proatherogenic hyperpermeability in aortic ECs. Treatment of cultured ECs with oxidized LDL, lysophosphatidylcholine, or LDL pretreated with secreted phospholipase A(2) led to the induction of m-calpain but not of μ-calpain, thereby eliciting selective m-calpain overactivation. These data suggest that lysophosphatidylcholine-induced m-calpain directly cleaves a juxtamembrane region of VE-cadherin, resulting in dissociation of β-catenin from the VE-cadherin complex, disorganization of adherence junctions, and hyperpermeability in ECs. CONCLUSIONS: Subtype-selective induction of m-calpain in aortic ECs during atherosclerotic progression is associated with proteolytic disorganization of VE-cadherin and proatherogenic hyperpermeability in cells. Thus, a strategy to selectively inhibit m-calpain may be useful for the therapeutic treatment of patients with atherosclerosis.
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Miyazaki et al. (2011) studied Atherosclerosis. Calpain inhibitors and m-calpain siRNA was evaluated on Atherosclerotic lesion development, proinflammatory responses, and VE-cadherin disorganization. Administration of calpain inhibitors or m-calpain siRNA attenuated atherosclerotic lesion development, proinflammatory responses, and VE-cadherin disorganization in mouse models.
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