title: m-Calpain induction in vascular endothelial cells on human and mouse atheromas and its roles in VE-cadherin disorganization and atherosclerosis.
abstract: 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.
  
  
  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.
authors: Department of Biochemistry, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, Japan. taku@pharm.showa-u.ac.jp
authors: Takuro
authors: T
authors: Miyazaki
authors: Yoshitaka
authors: Y
authors: Taketomi
authors: Masafumi
authors: M
authors: Takimoto
authors: Xiao-Feng
authors: XF
authors: Lei
authors: Shigeko
authors: S
authors: Arita
authors: Joo-ri
authors: JR
authors: Kim-Kaneyama
authors: Satoru
authors: S
authors: Arata
authors: Hisayuki
authors: H
authors: Ohata
authors: Hidekazu
authors: H
authors: Ota
authors: Makoto
authors: M
authors: Murakami
authors: Akira
authors: A
authors: Miyazaki
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001011:Aorta / Q000166:cytology; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism*; D002199:Capillary Permeability / Q000502:physiology; D018450:Disease Progression; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008875:Middle Aged; D058226:Plaque, Atherosclerotic / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D001057:Apolipoproteins E; D015820:Cadherins; D002154:Calpain; D008244:Lysophosphatidylcholines; D034741:RNA, Small Interfering; D011973:Receptors, LDL; D000099152:Cadherin 5; C449000:m-calpain; C569870:CAPN2 protein, human