Apelin expression deficiency in mice contributes to vascular stiffening by extracellular matrix remodeling of the aortic wall (original) (raw)
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2021
Vascular stiffness is often the main cause of arterial hypertension and its complications including atherosclerosis, observed during obesity. However, the mechanisms leading to this rigidity or the preventing factors are misknown. We hypothesized that apelin, known for its beneficial effects on lipid, inflammatory, and vascular metabolism, could be a protective factor against vascular stiffness. We used mice deficient for the apelin gene (KO-APL) and compared with wild-type mice (WT) at the level of metabolic markers and inflammations of white adipose tissue (WAT), as well as aortic functional and anatomical parameters. KO-APL mice developed an inflammation associated with significant remodeling of WAT, in particular with the protease expressions such as neutrophil elastase or cathepsin S. From a vascular point of view, these same elastases are involved in the fragmentation of elastic fibers, explaining the increase in vascular velocity of pulse wave and arterial hypertension. Inter...
Cardiovascular Pathology, 2014
Introduction: Adipose tissue is considered an endocrine organ, producing bioactive peptides, called adipokines. Adipokines produced by periadventitial fat have been implicated in the pathogenesis of vascular disease, including atherosclerosis. Adiponectin has established antiatherogenic actions, while the role of Tcadherin as an adiponectin receptor is not fully elucidated. The apelinergic system, consisting of apelin and its APJ receptor, is a mediator of various cardiovascular functions and may also be involved in the atherosclerotic process. We investigated the protein expression of adiponectin, T-cadherin, apelin and APJ in human aortas, coronary vessels, and the respective periadventitial adipose tissue and correlated their expression with the presence of atherosclerosis and clinical parameters. Methods: Immunohistochemistry for adiponectin, T-cadherin, apelin, and APJ was performed on human aortic and coronary artery samples including the periadventitial adipose tissue. Aortic and coronary atherosclerotic lesions were assessed using the american heart association (AHA) classification. Results: Adiponectin immunostaining, of varied intensity, was detected only in adipocytes, while T-cadherin was localized to vascular smooth muscle cells (VSMCs) and endothelial cells. Apelin immunostaining was detected in adipocytes, VSMCs, endothelial cells, and foam cells in atherosclerotic lesions, while APJ was found in VSMCs and endothelia. Periadventitial adiponectin and VSMC T-cadherin expression were negatively correlated with atherosclerosis in both sites, as was VSMC apelin expression. Several otherdepot specificassociations were observed. Conclusions: Our results suggest a possible role for T-cadherin as a mediator of antiatherogenic adiponectin actions, while they support the putative antiatherogenic profile for apelin and its APJ receptor in human arteries. Further research is absolutely necessary to confirm these notions. Summary: Periadventitial adipose tissue adipokines are implicated in vascular physiology and pathology. Adiponectin/T-cadherin and apelin/APJ immunoreactivity is detected in human aortas and coronary arteries. Adiponectin/T-cadherin and apelin/APJ expression patterns were found to be inversely associated with human aortic and coronary atherosclerosis.
The FASEB Journal, 2008
Adipose tissue is an active endocrine organ that produces a variety of secretory factors involved in the initiation of angiogenic processes. The bioactive peptide apelin is the endogenous ligand of the G protein-coupled receptor, APJ. Here we investigated the potential role of apelin and its receptor, APJ, in the angiogenic responses of human endothelial cells and the development of a functional vascular network in a model of adipose tissue development in mice. Treatment of human umbilical vein endothelial cells with apelin dose-dependently increased angiogenic responses, including endothelial cell migration, proliferation, and Matrigel ® capillary tubelike structure formation. These endothelial effects of apelin were due to activation of APJ, because siRNA directed against APJ, which led to long-lasting down-regulation of APJ mRNA, abolished cell migration induced by apelin in contrast to control nonsilencing siRNA. Hypoxia upregulated the expression of apelin in 3T3F442A adipocytes, and we therefore determined whether apelin could play a role in adipose tissue angiogenesis in vivo. Epididymal white adipose tissue (EWAT) transplantation was performed as a model of adipose tissue angiogenesis. Transplantation led to increased apelin mRNA levels 2 and 5 days after transplantation associated with tissue hypoxia, as evidenced by hydroxyprobe staining on tissue sections. Graft revascularization evolved in parallel, as the first functional vessels in EWAT grafts were observed 2 days after transplantation and a strong angiogenic response was apparent on day 14. This was confirmed by determination of graft hemoglobin levels, which are indicative of functional vascularization and were strongly increased 5 and 14 days after transplantation. The role of apelin in the graft neovascularization was then assessed by local delivery of stable complex apelin-targeting siRNA leading to dramatically reduced apelin mRNA levels and vascularization (quantified by hemogloblin content) in grafted EWAT on day 5 when compared with control siRNA. Taken together, our data provide the first evidence that apelin/APJ signaling pathways play a critical role in the development of the functional vascular network in adipose tissue. In addition, we have shown that adipocyte-derived apelin can be up-regulated by hypoxia. These findings provide novel insights into the complex relationship between adipose tissue and endothelial vascular function and may lead to new therapeutic strategies to modulate angiogenesis.-/APJ signaling system: a potential link between adipose tissue and endothelial angiogenic processes. FASEB J. 22, 4146 -4153 (2008)
Requirement of Apelin-Apelin Receptor System for Oxidative Stress-Linked Atherosclerosis
The American Journal of Pathology, 2007
The recently identified endogenous peptide apelin and its specific apelin receptor (APJ) are currently being considered as potential regulators in vascular tissue. Previously, we reported apelin mediates phosphorylation of myosin light chain and elicits vasoconstriction in vascular smooth muscle. In this study, physiological roles of the apelin-APJ system were investigated on atherosclerosis. In APJ and apolipoprotein E double-knockout (APJ ؊/؊ ApoE ؊/؊ ) mice fed a high-cholesterol diet, atherosclerotic lesions were dramatically reduced when compared with APJ ؉/؉ ApoE ؊/؊ mice, in the absence of an effect of cholesterol levels. Immunohistochemical detection of smooth muscle cells , using a smooth muscle ␣-actin antibody , showed greatly reduced staining for these cells in lesions of APJ ؊/؊ ApoE ؊/؊ mice fed a highcholesterol diet. Vascular production of superoxide radicals and the expression of nicotinamide-adenine dinucleotide phosphate oxidase subunits were decreased in APJ ؊/؊ ApoE ؊/؊ mice compared with APJ ؉/؉ ApoE ؊/؊ mice fed a standard normal diet. In vascular smooth muscle cells , apelin induced nicotinamide-adenine dinucleotide phosphate oxidase subunit expression. Apelin also induced vascular smooth muscle cell proliferation , which was inhibited by superoxide dismutase or diphenylene iodonium. The apelin-APJ system is a mediator of oxi-dative stress in vascular tissue , and thus we propose it to be a critical factor in atherogenesis under high-cholesterol dietary conditions. APJ deficiency is preventative against oxidative stresslinked atherosclerosis.
Effect of High-Fat Diet upon Inflammatory Markers and Aortic Stiffening in Mice
BioMed Research International, 2014
Changes in lifestyle such as increase in high-fat food consumption are an important cause for vascular diseases. The present study aimed to investigate the involvement of ACE and TGF-βin the aorta stiffness induced by high-fat diet. C57BL/6 male mice were divided in two groups according to their diet for 8 weeks: standard diet (ST) and high-fat diet (HF). At the end of the protocol, body weight gain, adipose tissue content, serum lipids and glucose levels, and aorta morphometric and biochemical measurements were performed. Analysis of collagen fibers by picrosirius staining of aorta slices showed that HF diet promoted increase of thin (55%) and thick (100%) collagen fibers deposition and concomitant disorganization of these fibers orientations in the aorta vascular wall (50%). To unravel the mechanism involved, myeloperoxidase (MPO) and angiotensin I converting enzyme (ACE) were evaluated by protein expression and enzyme activity. HF diet increased MPO (90%) and ACE (28%) activities...
Beneficial Effects of Apelin on Vascular Function in Patients With Central Obesity
Hypertension, 2017
Patients with central obesity have impaired insulin-stimulated vasodilation and increased ET-1 (endothelin 1) vasoconstriction, which may contribute to insulin resistance and vascular damage. Apelin enhances insulin sensitivity and glucose disposal but also acts as a nitric oxide (NO)–dependent vasodilator and a counter-regulator of AT 1 (angiotensin [Ang] II type 1) receptor–induced vasoconstriction. We, therefore, examined the effects of exogenous (Pyr 1 )apelin on NO-mediated vasodilation and Ang II– or ET-1–dependent vasoconstrictor tone in obese patients. In the absence of hyperinsulinemia, forearm blood flow responses to graded doses of acetylcholine and sodium nitroprusside were not different during saline or apelin administration (both P >0.05). During intra-arterial infusion of regular insulin, however, apelin enhanced the vasodilation induced by both acetylcholine and nitroprusside (both P <0.05). Interestingly, the vasodilator effect of concurrent blockade of AT 1 (...
BACKGROUND: Arterial stiffness and carotid intima-media thickness (IMT) constitute validated cardiovascular prognostic markers. Adiponectin and its receptors 1 (AdipoR1) and 2 (AdipoR2) are involved in coronary artery disease (CAD). We investigated whether AdipoR1 and R2 mRNA and protein expression are associated with arterial stiffness, IMT and extent of coronary atherosclerosis. METHODS: We studied 71 patients (61 men, 10 women) with angiographically proven CAD. We measured: (i) monocyte expression of AdipoR1 and AdipoR2 mRNA (quantitative real-time PCR) and protein expression (flow cytometry) (iii) adiponectin, metalloproteinase-9 (MMP-9) and C-reactive protein (CRP) blood levels, (iv) carotid-femoral artery pulse wave velocity (PWV) and carotid IMT. RESULTS: Patients with multi-vessel CAD had higher AdipoR1 and AdipoR2 mRNA than those with single-vessel (P < 0.05). PWV was associated with AdipoR1 mRNA (r = 0.474), AdipoR1 protein (r = 0.228), AdipoR2 mRNA (r = 0.716), AdipoR2-protein (r = 0.261), adiponectin (r = 0.236), and MMP-9 (r = 0.350) (P < 0.05, for all correlations). After adjustment for age, sex, waist-hip ratio, and mean blood pressure both AdipoR1 and AdipoR2 mRNA remained independent determinants of PWV (R(2) = 0.35 and R(2) = 0.57, P < 0.05). IMT was also associated with AdipoR2 mRNA, AdipoR2 protein, and MMP-9 (P < 0.05). Increased expression of ADR2 mRNA significantly related to MMP-9 (r = 0.210), and CRP (r = 0.531) (P < 0.05). CONCLUSION: Increased mRNA and protein expression of adiponectin receptors is related with increased aortic stiffness, coronary and peripheral atherosclerosis in patients with CAD. The interrelation of AdipoR2 with inflammatory markers, PWV and IMT suggests a compensatory increase of these receptors to counteract the excess inflammatory and atherogenic process in CAD. Thus, adiponectin receptors may provide a potential therapeutic target of agents activating their beneficial action.American Journal of Hypertension 2012; doi:10.1038/ajh.2012.42.
Blood Pressure, 2013
Epicardial adipose tissue (EAT), localized beneath the visceral pericardium, is a metabolically active endocrine and paracrine organ with possible interactions within the heart. Recent studies identified possible roles of uric acid (UA)-induced oxidative stress and increased inflammatory status in the pathogenesis of ascending aortic dilatation. The aim of this study was to investigate whether EAT is an independent factor for ascending aortic dilatation. The patients were evaluated by a complete transthoracic echocardiographic examination including measurements of EAT and aortic dimensions. Serum levels of UA and C-reactive protein and EAT thicknesses were compared in 38 patients with dilated ascending aorta (DAA) (the diameter ≥ 37 mm) vs. 107 subjects with normal aortic diameter (AD) of < 37 mm. EAT thickness was significantly higher in DAA group compared to normal AD group (8.3 ± 2.7 vs. 5.4 ± 2.2 mm, p < 0.001) as well as age (53 ± 10 vs. 48 ± 9 years, p = 0.004), the presence of hypertension (54% vs. 30%, p = 0.009) and UA levels (6.0 ± 1.4 vs. 5.2 ± 1.1 mg/dL, p < 0.001). There was a strong correlation between EAT thickness and ascending aortic diameter (r = 0.521, p < 0.001). In multiple logistic regression analysis, EAT thickness (OR: 1.429, p = 0.006), body mass index (OR: 1.169, p = 0.014) and UA levels (OR: 1.727, p = 0.023) were independently correlated to ascending aortic dilatation. We therefore propose that increased EAT thickness is an independent predictor of ascending aortic dilation.
Clinical Science
The aim of this study was to evaluate the effect of Compound 21 (C21), a selective AT2R agonist, on the prevention of endothelial dysfunction, extracellular matrix (ECM) remodeling and arterial stiffness associated with diet-induced obesity (DIO). 5-week-old male C57BL/6J mice were fed a standard (Chow) or high-fat diet (HF) for 6 weeks. Half of the animals of each group were simultaneously treated with C21 (1mg/kg/day, in the drinking water), generating 4 groups: Chow C, Chow C21, HF C, HF C21. Vascular function and mechanical properties were determined in the abdominal aorta. To evaluate ECM remodeling, collagen deposition, activity of metalloproteinases (MMP) 2 and 9 and TGF-b1 concentration were analyzed in the plasma. Abdominal aortas from HF C mice showed endothelial dysfunction as well as enhanced contractile but reduced relaxant responses to Ang II. This effect was abrogated with C21 treatment by preserving NO availability. A left-shift in the tension-stretch relationship, ...