Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ischemic tolerance decreases with aging, and the cardioprotective effect of ischemic preconditioning (IPC) is impaired in middle-aged animals. We have demonstrated that short-term caloric restriction (CR) improves myocardial ischemic tolerance in young and old animals via the activation of adiponectin-AMP-activated protein kinase (AMPK)-mediated signaling. However, it is unknown whether prolonged CR confers cardioprotection in a similar manner. Furthermore, little is known regarding the myocardial expression of silent information regulator 1 (Sirt1; which reportedly mediates various aspects of the CR response) with prolonged CR. Thus, 6-mo-old male Fischer-344 rats were randomly divided into ad libitum (AL) and CR groups. Six months later, isolated perfused hearts were subjected to 25 min of global ischemia followed by 120 min of reperfusion with or without IPC. CR improved the recovery of left ventricular function and reduced infarct size after ischemia-reperfusion and restored the IPC effect. Serum adiponectin levels increased, but myocardial levels of total and phosphorylated AMPK did not change with prolonged CR. Total levels of Sirt1 did not change with CR; however, in the nuclear fraction, CR significantly increased Sirt1 and decreased acetyl-histone H3. Eleven rats from each group were given N-nitro-l-arginine methyl ester in their drinking water for 4 wk before death. In these hearts, chronic inhibition of nitric oxide synthase prevented the increase in nuclear Sirt1 content by CR and abrogated CR-induced cardioprotection. These results demonstrate that 1) prolonged CR improves myocardial ischemic tolerance and restores the IPC effect in middle-aged rats and 2) CR-induced cardioprotection is associated with a nitric oxide-dependent increase in nuclear Sirt1 content.
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PMID:Impact of 6-mo caloric restriction on myocardial ischemic tolerance: possible involvement of nitric oxide-dependent increase in nuclear Sirt1. 1893 Oct 29

Caloric restriction (CR) can extend longevity and modulate the features of obesity-related metabolic and vascular diseases. However, the functional roles of CR in regulation of revascularization in response to ischemia have not been examined. Here we investigated whether CR modulates vascular response by employing a murine hindlimb ischemia model. Wild-type (WT) mice were randomly divided into two groups that were fed either ad libitum (AL) or CR (65% of the diet consumption of AL). Four weeks later, mice were subjected to unilateral hindlimb ischemic surgery. Body weight of WT mice fed CR (CR-WT) was decreased by 26% compared with WT mice fed AL (AL-WT). Revascularization of ischemic hindlimb relative to the contralateral limb was accelerated in CR-WT compared with AL-WT as evaluated by laser Doppler blood flow and capillary density analyses. CR-WT mice had significantly higher plasma levels of the fat-derived hormone adiponectin compared with AL-WT mice. In contrast to WT mice, CR did not affect the revascularization of ischemic limbs of adiponectin-deficient (APN-KO) mice. CR stimulated the phosphorylation of endothelial nitric-oxide synthase (eNOS) in the ischemic limbs of WT mice. CR increased plasma adiponectin levels in eNOS-KO mice but did not stimulate limb perfusion in this strain. CR-WT mice showed enhanced phosphorylation of AMP-activated protein kinase (AMPK) in ischemic muscle, and administration of AMPK inhibitor compound C abolished CR-induced increase in limb perfusion and eNOS phosphorylation in WT mice. Our observations indicate that CR can promote revascularization in response to tissue ischemia via an AMPK-eNOS-dependent mechanism that is mediated by adiponectin.
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PMID:Caloric restriction stimulates revascularization in response to ischemia via adiponectin-mediated activation of endothelial nitric-oxide synthase. 1899 Jun 85

Adiponectin is an abundant plasma protein secreted from adipocytes that elicits protective effects in the vasculature and myocardium. In obesity and insulin-resistant states, adiponectin levels are reduced and loss of its protective effects might contribute to the excess cardiovascular risk observed in these conditions. Adiponectin ameliorates the progression of macrovascular disease in rodent models, consistent with its correlation with improved vascular outcomes in epidemiological studies. The mechanisms of adiponectin signaling are multiple and vary among its cellular sites of action. In endothelial cells, adiponectin enhances production of nitric oxide, suppresses production of reactive oxygen species, and protects cells from inflammation that results from exposure to high glucose levels or tumor necrosis factor, through activation of AMP-activated protein kinase and cyclic AMP-dependent protein kinase (also known as protein kinase A) signaling cascades. In the myocardium, adiponectin-mediated protection from ischemia-reperfusion injury is linked to cyclo-oxygenase-2-mediated suppression of tumor necrosis factor signaling, inhibition of apoptosis by AMP-activated protein kinase, and inhibition of excess peroxynitrite-induced oxidative and nitrative stress. In this Review, we provide an update of studies of the signaling effects of adiponectin in endothelial cells and cardiomyocytes.
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PMID:Protective vascular and myocardial effects of adiponectin. 1902 92

The fat-derived hormone adiponectin has been shown to have a protective role in macrovascular disorders. However, nothing is known about the function of adiponectin in retinal microvessel disease. Here, we investigated the causal role of adiponectin in retinal vessel formation and inflammation under conditions of hypoxia. When neonatal mice were subjected to ischemia-induced retinopathy, pathological retinal neovascularization during ischemia was exacerbated in adiponectin-knockout (APN-KO) mice compared with wild-type mice (neovascular area: 17.0+/-1.0% versus 11.7+/-0.6%, respectively). APN-KO mice also exhibited increased leukocyte adhesion (2.3+/-0.4-fold) and tumor necrosis factor (TNF)-alpha expression (2.6+/-0.2-fold) in hypoxic retina. Adenovirus-mediated overexpression of adiponectin attenuated hypoxia-induced pathological retinal neovascularization by 35% in wild-type mice and by 40% in APN-KO mice and leukostasis by 64% in wild-type mice and by 75% in APN-KO mice, which were associated with reduced TNF-alpha production. TNF-alpha blockade diminished the enhanced pathological neovascularization in APN-KO mice by 34%, and the inhibitory effects of adiponectin overexpression on retinal neovascularization and leukocyte adhesion were abolished in mice lacking TNF-alpha. These data provide evidence that adiponectin protects against retinal vessel injury following pathological stimuli through modulation of TNF-alpha inflammatory responses.
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PMID:Adiponectin suppresses pathological microvessel formation in retina through modulation of tumor necrosis factor-alpha expression. 1942 59

Adiponectin is a fat-derived plasma protein that has cardioprotective roles in obesity-linked diseases. Because cyclooxygenase 2 (COX-2) is an important modulator of endothelial function, we investigated the possible contribution of COX-2 to adiponectin-mediated vascular responses in a mouse hind limb model of vascular insufficiency. Ischemic insult increased COX-2 expression in endothelial cells of wild-type mice, but this induction was attenuated in adiponectin knockout mice. Ischemia-induced revascularization was impaired in mice in which the Cox-2 gene is deleted in Tie2-Cre-expressing cells. Adenovirus-mediated overexpression of adiponectin enhanced COX-2 expression and revascularization of ischemic limbs in control mice, but not in targeted Cox-2-deficient mice. In cultured endothelial cells, adiponectin protein increased COX-2 expression, and ablation of COX-2 abrogated the adiponectin-stimulated increases in endothelial cell migration, differentiation, and survival. Ablation of calreticulin (CRT) or its adaptor protein CD91 diminished adiponectin-stimulated COX-2 expression and endothelial cell responses. These observations provide evidence that adiponectin promotes endothelial cell function through CRT/CD91-mediated increases in COX-2 signaling. Thus, disruption of the adiponectin-COX-2 regulatory axis in endothelial cells could participate in the pathogenesis of obesity-related vascular diseases.
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PMID:Adiponectin promotes revascularization of ischemic muscle through a cyclooxygenase 2-dependent mechanism. 1939 82

It has been reported that dietary energy restriction, including intermittent fasting (IF), can protect heart and brain cells against injury and improve functional outcome in animal models of myocardial infarction (MI) and stroke. Here we report that IF improves glycemic control and protects the myocardium against ischemia-induced cell damage and inflammation in rats. Echocardiographic analysis of heart structural and functional variables revealed that IF attenuates the growth-related increase in posterior ventricular wall thickness, end systolic and diastolic volumes, and reduces the ejection fraction. The size of the ischemic infarct 24 h following permanent ligation of a coronary artery was significantly smaller, and markers of inflammation (infiltration of leukocytes in the area at risk and plasma IL-6 levels) were less, in IF rats compared to rats on the control diet. IF resulted in increased levels of circulating adiponectin prior to and after MI. Because recent studies have shown that adiponectin can protect the heart against ischemic injury, our findings suggest a potential role for adiponectin as a mediator of the cardioprotective effect of IF.
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PMID:Cardioprotective effect of intermittent fasting is associated with an elevation of adiponectin levels in rats. 1942 20

Angiogenic cell therapy with the transplantation of endothelial progenitor cells (EPC) or bone marrow mononuclear cells (BM-MNC) receives considerable attention as an approach to revascularize ischemic tissues. Adiponectin is a circulating hormone produced by the apM1 gene in adipocytes. Adiponectin modulates lipid metabolism and obesity, and it was recently found to promote physiological angiogenesis in response to ischemia. Patients with multiple cardiovascular disease risk factors or myocardial infarction may benefit from progenitor cell therapy, but they display depressed adiponectinemia. We hypothesized that adiponectin stimulation of transplanted cells is critical for their pro-angiogenic function. We aimed to establish whether adiponectinemia in the cell donor or in the cell recipient determines the success of pro-angiogenic cell therapy. In vitro, we found that conditioned media derived from wild-type adipocytes (adipo-CM) or purified adiponectin strongly enhanced BM-MNC survival and proliferation and stimulated EPC differentiation, whereas adipo-CM from apM1-/- adipocytes was one-half less effective. On the other hand, wild-type and apM1-/- BM-MNC displayed similar resistance to apoptosis and proliferation rates. In vivo, wild-type, and apM1-/- BM-MNC induced similar angiogenic reactions in wild-type ischemic hindlimbs. In contrast, wild-type BM-MNC had much diminished effects in apM1-/- ischemic hindlimbs. We concluded that adiponectin enhances BM-MNC survival and proliferation, and adiponectinemia in the cell therapy recipient is essential for the pro-angiogenic benefits of cell therapy. These observations imply that progenitor cell transplantation might only induce angiogenesis in patients with high adiponectinemia.
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PMID:Adiponectinemia controls pro-angiogenic cell therapy. 1978 8

In this review, we focus on the role of adiponectin as a cardioprotective agent in several pathological heart conditions. Obesity is closely associated with Type 2 diabetes, hypertension and heart disease. Adiponectin is an adipose tissue-derived hormone whose concentration is downregulated in subjects with obesity-related diseases. Hypoadiponectinemia has been identified as an independent risk factor for Type 2 diabetes, coronary artery disease, acute coronary syndrome and hypertension. More recent experimental findings have shown that adiponectin directly affects signaling in cardiac myocytes and has beneficial effects on several pathological heart conditions, including cardiac hypertrophy and myocardial infarction. The favorable effects of adiponectin are associated with attenuated inflammatory response, decreased myocyte death, decreased hypertrophic response, maintained ischemia-induced angiogenesis and reduced interstitial fibrosis. Therefore, adiponectin could represent a molecular target for treating obesity-linked cardiac diseases.
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PMID:Potential of adiponectin as a cardioprotective agent. 1980 85

It has recently been recognized that adiponectin protects the vasculature and prevents atherosclerotic change through AMP-activated protein kinase (AMPK) activation, and some of its molecular mechanisms have been clarified. AMPK, which might be a therapeutic target of metabolic abnormality, is a serine-threonine kinase, heterotrimer protein composed of three subunits of alpha, beta and gamma. It is activated by an upper kinase LKB1 and an increase in the AMP/ATP ratio. Some anabolic enzymes are directly phosphorylated and inhibited, suggesting that AMPK suppresses ATP consumption by negatively regulating the synthetic pathway. The LKB1-AMPK pathway is pivotal for controlling cellular polarity and mitosis. Furthermore, AMPK has been associated with cellular autophagy. AMPK activation could induce autophagy and prolong a period leading to cell apoptosis. Apoptosis under anoxic conditions was decreased when newly constructed, constitutively active mutants of AMPK-alpha were overexpressed in vascular endothelial cells. AMPK could inhibit the growth of vascular smooth muscle through MEK-ERK pathway inhibition. After ischemia reperfusion, dominant-negative AMPK overexpression inhibits cardiac function through the suppression of glucose uptake and fatty acid beta-oxidation in cardiac myocytes. Cardiac hypertrophy with accumulation of glycogen granules because of gene mutation of gamma2 associated with the Wolff-Parkinson-White syndrome has been considered an activated type in most cases. It is necessary to clarify the tissue-specific and stress-specific activation mechanism of AMPK.
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PMID:The role of AMP-activated protein kinase in the cardiovascular system. 1991 Oct 4

The ultrasensitive energy sensor AMP-activated protein kinase (AMPK) orchestrates the regulation of energy-generating and energy-consuming pathways. AMPK is highly expressed in the kidney where it is reported to be involved in a variety of physiological and pathological processes including ion transport, podocyte function, and diabetic renal hypertrophy. Sodium transport is the major energy-consuming process in the kidney, and AMPK has been proposed to contribute to the coupling of ion transport with cellular energy metabolism. Specifically, AMPK has been identified as a regulator of several ion transporters of significance in renal physiology, including the cystic fibrosis transmembrane conductance regulator (CFTR), the epithelial sodium channel (ENaC), the Na(+)-K(+)-2Cl(-) cotransporter (NKCC), and the vacuolar H(+)-ATPase (V-ATPase). Identified regulators of AMPK in the kidney include dietary salt, diabetes, adiponectin, and ischemia. Activation of AMPK in response to adiponectin is described in podocytes, where it reduces albuminuria, and in tubular cells, where it reduces glycogen accumulation. Reduced AMPK activity in the diabetic kidney is associated with renal accumulation of triglyceride and glycogen and the pathogenesis of diabetic renal hypertrophy. Acute renal ischemia causes a rapid and powerful activation of AMPK, but the functional significance of this observation remains unclear. Despite the recent advances, there remain significant gaps in the present understanding of both the upstream regulating pathways and the downstream substrates for AMPK in the kidney. A more complete understanding of the AMPK pathway in the kidney offers potential for improved therapies for several renal diseases including diabetic nephropathy, polycystic kidney disease, and ischemia-reperfusion injury.
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PMID:Role of the energy sensor AMP-activated protein kinase in renal physiology and disease. 2018 68


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