Adiponectin association with T‐cadherin protects against neointima proliferation and atherosclerosis

Abstract

Adiponectin, an adipocyte-derived protein abundant in the circulation, is thought to be protective against atherosclerosis. However, it is not fully understood how the association of adiponectin with vascular cells and its antiatherogenic effect are connected. In this study, T-cadherin was essential for accumulation of adiponectin in the neointima and atherosclerotic plaque lesions, and the adiponectin-T-cadherin association protected against vascular injury. In the apolipoprotein E-knockout (ApoE-KO) mice, adiponectin and T-cadherin colocalized on endothelial cells and synthetic smooth muscle cells in the aortic intima. Notably, aortic adiponectin protein disappeared in T-cadherin/ApoE double-knockout (Tcad/ApoE-DKO) mice with significant elevation of blood adiponectin concentration. Furthermore, in Tcad/ApoE-DKO mice, carotid artery ligation resulted in a significant increase of neointimal thickness compared with ApoE-KO mice. Finally, on a high-cholesterol diet, Tcad/ApoE-DKO mice increased atherosclerotic plaque formation, despite a 5-fold increase in plasma adiponectin level compared with that in ApoE-KO mice. , knockdown of T-cadherin from human aortic smooth muscle cells (HASMCs) with synthetic phenotype significantly reduced adiponectin accumulation on HASMCs and negated the inhibitory effect of adiponectin on proinflammatory change. Collective evidence showed that adiponectin accumulates in the vasculature T-cadherin, and the adiponectin-T-cadherin association plays a protective role against neointimal and atherosclerotic plaque formations.-Fujishima, Y., Maeda, N., Matsuda, K., Masuda, S., Mori, T., Fukuda, S., Sekimoto, R., Yamaoka, M., Obata, Y., Kita, S., Nishizawa, H., Funahashi, T., Ranscht, B., Shimomura, I. Adiponectin association with T-cadherin protects against neointima proliferation and atherosclerosis.

Adiponectin/T-cadherin system enhances exosome biogenesis and decreases cellular ceramides by exosomal release

“…Recent studies have shown that the active forms, multimeric and hexameric adiponectin, accumulate in tissues such as heart, vascular endothelium, and skeletal muscles through interaction with T-cadherin, a unique glycosylphosphatidylinositol-anchored (GPI-anchored) cadherin (7)(8)(9). Importantly, we recently showed that adiponectin suppressed neointimal and atherosclerotic plaque formations through T-cadherin (10). Other groups have also shown the significance of adiponectin/T-cadherin association in cardiovascular protection (7,8).…”

Role of Adipokines in Cardiovascular Disease

“…Since leptin, a central regulator of food intake and energy expenditure, was demonstrated to be an adipose-specific adipokine, great attention has been given to the identification and characterization with the tethering molecule T-cadherin, APN accumulates in the vascular wall. 29 These in vivo data suggest that APN protects against various obesity-inducible vascular diseases such as atherosclerosis, vascular dysfunction, and hypertension by its interaction with vascular component cells.…”

Interorgan communication by exosomes, adipose tissue, and adiponectin in metabolic syndrome

“…The adiponectin-mediated production of exosomes also may also affect whole-body glucose metabolism. tion by adiponectin may require T-cadherin and consumption of adiponectin through T-cadherin binding (14)(15)(16)98). Low tissue T-cadherin and/or low T-cadherin-mediated consumption of adiponectin may result in poor CHF prognosis.…”

“…As we discuss below, organ protec- Clinical analyses have demonstrated that HMW multimeric adiponectin is the active form, and it exerts various pleiotropic effects (64)(65)(66)(67). Recent studies have shown that the active HMW multimers and hexamers of adiponectin accumulate in tissues such as heart, vascular endothelium, and skeletal muscles through interaction with T-cadherin (14)(15)(16)(17)98). Plasma adiponectin increased more than 3-fold in T-cadherin-KO mice compared with WT mice, with a dramatic increase of HMW multimeric adiponectin (98).…”

“…Several recent studies have reported that T-cadherin mediates cardiovascular protection and skeletal muscle regeneration via the clinically important high molecular weight (HMW) multimeric adiponectin (14)(15)(16)(17). T-cadherin facilitates adiponectin accumulation in multivesicular bodies, a subtype of endosome in which exosomes are generated, wherein adiponectin stimulates exosome biogenesis and secretion (17)(18)(19).…”