Selective Suppression of Endothelial Cell Apoptosis by the High Molecular Weight Form of Adiponectin

Abstract

Abstract-Adiponectin is an adipocyte-derived, antiatherogenic protein that is present in serum as three isoforms. Total adiponectin levels are decreased in obese or diabetic humans or animal models. This study was designed to elucidate the relative isoform distribution of adiponectin in human disease states and identify the active form of adiponectin toward vascular endothelial cells. The percentage of high molecular weight form (HMW) per total adiponectin was significantly lower in patients with coronary artery disease than control subjects, whereas the hexamer form was similar and the trimer form was significantly higher. During weight reduction in obese subjects, the HMW form increased and the trimer and hexamer forms decreased. Recombinant adiponectin dose-dependently suppressed apoptosis and caspase-3 activity in human umbilical vein endothelial cells (HUVECs). Transduction with dominant-negative AMP-activated protein kinase (AMPK) abolished the suppressive effect of adiponectin on HUVECs. Gel filtration chromatography was used to separate the adiponectin isoforms, and the antiapoptotic effect toward HUVECs was only observed with the HMW form. These data suggest that HMW adiponectin specifically confers the vascular-protective activities of this adipocytokine. A diponectin is abundantly present in human plasma (ranges 3 to 30 g/mL), and its levels are decreased in patients and animal models with obesity, diabetes, and coronary artery diseases. [1][2][3][4] Adiponectin has a number of vascular protective activities, 5-9 and it can promote angiogenesis by stimulating AMPK and Akt signaling in endothelial cells. 10 Collectively, these findings suggest that decreased plasma adiponectin levels during obesity and diabetes may contribute to vascular disease in these patients. Adiponectin is present in serum as a trimer, hexamer, or high molecular weight form. 11 The biological activities of these isoforms is controversial. Waki et al 12 has reported that the HMW isoform promotes AMP-activated protein kinase in hepatocytes. In contrast, Tsao et al 13 recently reported that only trimers activate AMPK in muscle, whereas hexamers and HMW forms activate NF-B. Differences in the tissuespecific expression patterns of two adiponectin receptors may contribute to these divergent activities. 14 Therefore, isoform abundance should be evaluated when examining the role of adiponectin in different disease states.Endothelial injury is considered to be a critical event in the pathogenesis of atherosclerosis, plaque erosion, and thrombus formation. 15 The turnover rates of endothelial cells (ECs) are accelerated in atherosclerosis-prone regions, and local EC apoptosis has been implicated in this process. 16 In patients with obesity-related disorders, EC injury could be caused by high glucose, tumor necrosis factor-␣, and oxidized lowdensity lipoprotein. [17][18][19] In contrast, little is known about antiatherogenic factors that could function to protect EC from apoptosis.In this study, we examined relative adiponectin isoform abun...

Adiponectin protects against the development of systolic dysfunction following myocardial infarction

“…In this study, the greater impaired LV function in adiponectin KO mice was accompanied by greater reductions in capillary density, whereas adenovirusmediated overexpression of adiponectin maintained capillary density in the infarct border zone. In accordance with these observations, we have previously shown that adiponectin can function as a survival factor for endothelial cells [41] and that APN-KO mice exhibit impaired angiogenic repair in ischemic hindlimbs whereas adiponectin overexpression stimulates blood vessel growth [14,42]. Thus, the ability of adiponectin to directly affect endothelial cell survival and stimulate vascularization may contribute to the maintenance of myocardial capillary density in response to chronic myocardial ischemia, resulting in the preservation of LV function.…”

Up-regulation of the anti-inflammatory adipokine adiponectin in acute liver failure in mice

“…However, further signaling pathways being involved in the anti-apoptotic effects of adiponectin in hepatocytes remain to be elucidated. The activation of the AMP-kinase for example has been shown to be involved in protection from mitogen-deprivation induced cell death in HUVEC [18].…”

The role of total and high-molecular-weight complex of adiponectin in vascular function in offspring whose parents both had type 2 diabetes

“…Indeed, the HMW isomer exhibits a stronger relationship to incident coronary artery disease [23] as well as to the insulin sensitising response to thiazolidinedione administration [22]. Furthermore only HMW adiponectin has been shown to suppresses apoptosis of endothelial cells [23], and formation of higher order complexes is necessary to promote AMP-activated protein kinase in hepatocytes [24]. Given these collective findings, it seems possible that studying total adiponectin may be insufficient to detect a potential relationship to vascular function and we chose to specifically assess the role of the HMW complexes in vascular function in vivo.…”

“…In brief, after an overnight fast and the collection of baseline samples, Dextrose 0.3 g/kg was administered intravenously, followed 20 min later by the intravenous infusion of insulin 0.03 U/kg (Humulin R; Eli Lilly, Indianapolis, IN, USA). Samples were collected for insulin and glucose at 2, 3, 4, 5,6,8,10,12,14,19,22,23,24,25,27,30,40,50,60,70,80, 90, 100, 120, 140, 160 and 180 min following the dextrose and analysed using the Bergman's Minimal Model, a computer-based method to assess plasma insulin and glucose dynamics during an IVGTT. The minimum model for glucose disposal and insulin dynamics yields assessments of insulin secretion and sensitivity, including the insulin sensitivity index (S I ) and the glucose effectiveness index (S G ) also known as insulin-independent glucose clearance.…”

“…However, the HMW complex is thought to have enhanced biological activity compared with the LMW. At the clinical level, only the percentage of HMW protein exhibits an inverse correlation with coronary artery disease [23]. In vitro, formation of higher order multimers is necessary to promote AMPactivated protein kinase in hepatocytes [24].…”