Role of Adipose Tissue Endothelial ADAM17 in Age-Related Coronary Microvascular Dysfunction

Abstract

Objective A disintegrin and metalloproteinase ADAM17 (TNF-α converting enzyme) regulates soluble TNF levels. We tested the hypothesis that aging-induced activation in adipose tissue (AT)-expressed ADAM17 contributes to the development of remote coronary microvascular dysfunction (CMD) in obesity. Approach and Results Coronary arterioles (CA,~90 μm) from right atrial appendages and mediastinal AT were examined in patients (age:69±11yrs.,BMI:30.2±5.6) who underwent open-heart surgery. CA and AT were also studied in 6-month and 24-month lean and obese mice fed a normal or high-fat diet (HFD). We found that obesity elicited impaired endothelium-dependent CA dilations only in older patients and in aged HFD mice. Transplantation of AT from aged obese, but not from young or aged mice increased serum cytokine levels, including TNF, and impaired CA dilation in the young recipient mice. In patients and mice obesity was accompanied by age-related activation of ADAM17, which was attributed to vascular endothelium-expressed ADAM17. Excess, ADAM17-shed TNF from AT arteries in older obese patients was sufficient to impair CA dilation in a bioassay in which the AT artery was serially connected to a CA. Moreover, we found that the increased activity of endothelial ADAM17 is mediated by a diminished inhibitory interaction with caveolin-1, owing to age-related decline in caveolin-1 expression in obese patients and mice or to genetic deletion of caveolin-1. Conclusions The present study indicates that aging and obesity cooperatively reduce Cav1 expression, increase vascular endothelial ADAM17 activity and soluble TNF release in AT, which may contribute to the development of remote CMD in older obese patients.

Role of Endothelial ADAM17 in Early Vascular Changes Associated with Diabetic Retinopathy

“…For example, previous studies have implicated ADAM17 in the regulation of several substrates involved in the pathogenesis of DR including TNFα, TNFRI/II, IL-6R, p75NTR, and ICAM-1 [9,10,[12][13][14][15][16]. Our data are consistent with previous reports showing that ADAM17 contributes to multiple vascular pathologies [28][29][30]. In particular, studies in brain microvascular endothelial cells demonstrated an important contribution of ADAM17 to vascular barrier impairment in response to hypoxia [32].…”

MicroRNA‐188 regulates aging‐associated metabolic phenotype

“…Aging is often accompanied by an irreversible decline in physiological function, especially metabolic function. The age‐associated metabolic phenotype, including decreased energy expenditure, increased fat mass accumulation, and insulin sensitivity deterioration (Guillory et al, ), can ultimately lead to age‐associated metabolic dysfunction, which correlates closely with several disease, such as type 2 diabetes (Lin et al, ), fatty liver (Gong, Tas, Yakar, & Muzumdar, ; Sheedfar et al, ), cardiovascular diseases (Dou et al, ), neurodegenerative diseases (Martocchia et al, ), and cancer (Topuz et al, ). Thus, exploring the underlying mechanisms of the age‐associated metabolic phenotype and developing drugs to treat aging‐associated metabolic dysfunction are of paramount importance.…”

Efferocytosis and Outside-In Signaling by Cardiac Phagocytes. Links to Repair, Cellular Programming, and Intercellular Crosstalk in Heart

“…In vascular smooth muscle cells, oxidized low-density lipoprotein in vitro or hyperlipidemia in vivo impaired phagocytosis of apoptotic cells leading to the development of secondary necrotic cells capable of releasing both IL-1α and IL-1β further propagating the inflammatory response. Mice maintained on a high-fat diet also displayed increased activation of ADAM17 on the vascular endothelium, indicating that proteolytic degradation of apoptotic receptors may contribute to impaired phagocytosis during obesity and hyperlipidemia ( 230 ). Targeting hyperlipidemia using atorvastatin, restored phagocytic function to retinal pigment epithelial cells treated with cholesterol crystals or oxidized low-density lipoproteins ( 231 ), demonstrating a proof-of-principle approach to mitigating detrimental effects of hyperlipidemia on phagocytosis in the heart.…”