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. 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 Ϫ/Ϫ ) mice. Furthermore, proteolytic disorganization of VE-cadherin was shown in aortic ECs in ldlr Ϫ/Ϫ and apolipoprotein E-deficient (apoE

Calpain and Atherosclerosis

“…In contrast, Takano et al recently revealed that conditional knockout mice, in which m-calpain is expressed in the placenta but not in the fetus, survive to adulthood 26) . Thus, m-calpain is unlikely to play an essential role in cardiovascular development in the fetus, but rather plays critical roles in placental integrity, since abnormalities in placental development have been shown to cause cardiovascular tension 4) and atherosclerotic vascular disease 7) . The biological implications of the differential roles of calpains under physiological and pro-atherogenic conditions remain unknown; however, we hypothesized that pathogenic mediators [e.g., modified low-density lipoprotein (LDL) in atherosclerosis, angiotensin Ⅱ in hypertension] lead calpains to an over-active state or otherwise abnormal elevation of expression, thereby accelerating pro-atherogenic conditions.…”

“…Interestingly, calpains are capable of promoting NF-κB signals via the degradation of IκBα without affecting phosphorylation of this inhibitor 33,34) . Since m-calpain is induced in ECs in atherosclerotic lesions 7) , it is not surprising that NF-κB signals are promoted in ECs during atherogenesis through calpain-induced degradation of IκBα. This hypothesis is consistent with our previous data: the expression levels of NF-κB as well as those of adhesion molecules or cytokines in the pro-atherogenic aorta in ldlr −/− mice decreased significantly following administration of the calpain inhibitors, calpeptin and calpain inhibitor Ⅱ .…”

“…An earlier investigation determined that aortic VE-cadherin, a dominant factor in EC barrier function, lacks organization in ApoE −/− mice during the development of atherosclerosis 43) . We recently established that VE-cadherin disorganization is due to direct proteolysis by m-calpain in aortic ECs 7) . Interestingly, the subtype-selective induction of m-calpain occurs simultaneously in the pro-atherogenic aorta in mice, a phenomenon restricted to ECs on atheroma rather than other component cells in atherosclerotic lesions (e.g., VSMCs or foam cells).…”

“…This observation is consistent with human atherosclerosis, since the EC-specific induction of m-calpain also occurs in atherosclerotic lesions in the human aorta. Given that down-regulation of VE-cadherin reportedly promotes extravasation of immunocompetent cells or macromolecules into the vascular wall 44,45) and that in vivo silencing of CAPN2 by siRNA results in the prevention of pro-atherogenic hyperpermeability in the murine aorta 7) , it is likely that m-calpain-induced disorganization of VE-cadherin in aortic ECs may accelerate the progression of atherosclerotic lesions.…”

“…Furthermore, the deleterious effects of calpains under conditions of cardiovascular disease, including hypertension 4) and diabetes mellitus 5,6) , have been proposed. Recently, several lines of evidence published by us 7) and others [8][9][10][11][12] indicated pathophysiological implications of calpain systems in atherosclerotic diseases, although calpains are likely to participate in the physiological regulation of the vessels 13) . Accordingly, this review highlights the physiological roles of calpain systems, as well as their proatherogenic properties.…”