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Adiponectin activated posthypoxic cardiomyocyte nuclear STAT3 and mitochondrial STAT3, respectively, via AMPK-dependent and AMPK-independent pathways. Isolated cardiomyocytes were subjected to hypoxia-reoxygenation (HR) with globular APN (gAd) in the absence or presence of AMPK inhibitor compound C (CC) or STAT3 inhibitor stattic. (a) Cardiomyocyte death assessed by lactate dehydrogenase (LDH) release. (b) Protein expression of cleaved and total caspase-3. (c) Representative images for TUNEL staining and dihydroethidium (DHE) staining. (d) Cell apoptosis assessed by TUNEL staining. (e) Cellular reactive oxygen species production assessed by DHE staining. (f) Representative images for western blotting. (g–i) Protein expression of phosphorylated and total AMPK, STAT3 (Ser727), and STAT3 (Tyr705). Data are mean±SEM of two independent experiments each performed in triplicate: ∗p<0.05 and ∗∗p<0.01.
Source publication
Myocardial ischemic postconditioning- (IPo-) mediated cardioprotection against myocardial ischemia-reperfusion (IR) injury needs the activation of signal transducer and activator of transcription 3 (STAT3), which involves adiponectin (APN). APN confers its biological effects through AMP-activated protein kinase- (AMPK-) dependent and AMPK-independe...
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Citations
... Under conditions of blockade of NF-κB activation, excessive activation of STAT-3 is possible due to alcohol-induced oxidative damage to liver cells [38]. Activated STAT-3 has the ability to reduce the production of superoxide anion radicals and increase the expression of antioxidant enzymes (superoxide dismutase and catalase) by activating nrf-2 [39]. Elevated concentrations of MDA may be associated with increased, relative to the control group, concentration of ONOOand decreased concentrations of H 2 S. ...
Alcohol-related liver disease is the most common cause of liver disease worldwide. The purpose of this work is the establishment of the influence of the transcription factor κB on the development of oxidative-nitrosative stress in the liver of rats under conditions of chronic alcohol intoxication. The experiments were performed on 24 male Wistar rats weighing 180-220 g. The animals were divided into 4 groups of 6 animals: control; animals, which were administered NF-κB inhibitor, namely ammonium pyrrolidinedithiocarbamate (PDTC) at a dose of 76 mg/kg 3 times a week; animals, on which we simulated alcoholic hepatitis and group of combination of alcoholic hepatitis and NF-κB inhibitor. We determined in rat liver homogenate the following biochemical parameters: the activity of NO synthase isoforms, superoxide dismutase and catalase activity, the concentration of malonic dialdehyde, the concentration of peroxynitrite, nitrites and nitrosothiols, concentration of sulfide anion and superoxide anion radical production. Chronic alcohol intoxication led to increased production of reactive oxygen and nitrogen species on the background of decreased antioxidant activity, thus intensifying lipid peroxidation in the liver. Blockade of the transcription factor κB during chronic alcohol intoxication despite an increase in antioxidant activity and decrease of reactive oxygen and nitrogen species production did not ameliorate oxidative damage to the liver. Blockade of activation of nuclear transcription factor κB in rat liver by PDTC reduced the risk of oxidative damage to hepatocytes, but did not reduce the risk of developing nitrosative damage to hepatocytes. Keywords: chronic alcohol intoxication, NF-κB, oxidative-nitrosative stress, PDTC, rat liver
... Zhu et al. demonstrated that APN enhances antioxidant capacity by activating AMPK-dependent STAT3 at Tyr705, and reduces ROS generation by activating AMPK-independent STAT3 at Ser727, conferring cardioprotection. Combining APN and ischemic post-conditioning (IPO) has synergistic protective effects against MI-R injury [113]. ...
... [103][104][105][106][107][108] Myocardial Ischemia/reperfusionand infarction Reduces oxidative stress and protects the heart in MI/R; works in T2DM state. [10,[110][111][112][113][114][115][116][117] Protects myocardial cells and improves microcirculation to prevent the occurrence and development of myocardial infarction; it also plays a role in T2DM state. [11,[119][120][121] Heart failure Biomarker for diagnosis and prognosis. ...
Lifestyle changes have led to increased incidence of cardiovascular disease (CVD); therefore, potential targets against CVD should be explored to mitigate its risks. Adiponectin (APN), an adipokine secreted by adipose tissue, has numerous beneficial effects against CVD related to glucose and lipid metabolism disorders, including regulation of glucose and lipid metabolism, increasing insulin sensitivity, reduction of oxidative stress and inflammation, protection of myocardial cells, and improvement in endothelial cell function. These effects demonstrate the anti-atherosclerotic and antihypertensive properties of APN, which could aid in improving myocardial hypertrophy, and reducing myocardial ischemia/reperfusion (MI/R) injury and myocardial infarction. APN can also be used for diagnosing and predicting heart failure. This review summarizes and discusses the role of APN in the treatment of CVD related to glucose and lipid metabolism disorders, and explores future APN research directions and clinical application prospects. Future studies should elucidate the signaling pathway network of APN cardiovascular protective effects, which will facilitate clinical trials targeting APN for CVD treatment in a clinical setting.
... Since its first discovery in 1995, both clinical and experimental studies have pointed to the function of APN and its receptors in preventing cardiovascular dysfunction and remodeling of the heart (184)(185)(186). It was revealed that the heart has a local APN signaling system, which is downregulated in the diabetic heart of animal models and in patients. ...
The diabetic population has been increasing in the past decades and diabetic cardiomyopathy (DCM), a pathology that is defined by the presence of cardiac remodeling and dysfunction without conventional cardiac risk factors such as hypertension and coronary heart diseases, would eventually lead to fatal heart failure in the absence of effective treatment. Impaired insulin signaling, commonly known as insulin resistance, plays an important role in the development of DCM. A family of integral membrane proteins named caveolins (mainly caveolin-1 and caveolin-3 in the myocardium) and a protein hormone adiponectin (APN) have all been shown to be important for maintaining normal insulin signaling. Abnormalities in caveolins and APN have respectively been demonstrated to cause DCM. This review aims to summarize recent research findings of the roles and mechanisms of caveolins and APN in the development of DCM, and also explore the possible interplay between caveolins and APN.
... In an experiment on male SpragueDawley rats, Zhu et al. investigated whether adiponectin improved post-MI remodeling and I/R injury through AMPK-dependent and independent AMPK STAT3 activation [182]. In the model of subacute CVB3 myocarditis, APN-KO mice exhibited a lower level of MMP-9 synthesized by cardiac fibroblasts, which impaired the collagen cleavage during the myocardium injury [183].Yan et al. showed that patients affected by hypertension with a lower level of adiponectin (resulting from genetic polymorphism) were predisposed to enhanced cardiac fibrosis [184]. ...
Obesity is a growing epidemiological problem, as two-thirds of the adult population are carrying excess weight. It is a risk factor for the development of cardiovascular diseases (hypertension, ischemic heart disease, myocardial infarct, and atrial fibrillation). It has also been shown that chronic obesity in people may be a cause for the development of heart failure with preserved ejection fraction (HFpEF), whose components include cellular hypertrophy, left ventricular diastolic dysfunction, and increased extracellular collagen deposition. Several animal models with induced obesity, via the administration of a high-fat diet, also developed increased heart fibrosis as a result of extracellular collagen accumulation. Excessive collagen deposition in the extracellular matrix (ECM) in the course of obesity may increase the stiffness of the myocardium and thereby deteriorate the heart diastolic function and facilitate the occurrence of HFpEF. In this review, we include a rationale for that process, including a discussion about possible putative factors (such as increased renin–angiotensin–aldosterone activity, sympathetic overdrive, hemodynamic alterations, hypoadiponectinemia, hyperleptinemia, and concomitant heart diseases). To address the topic clearly, we include a description of the fundamentals of ECM turnover, as well as a summary of studies assessing collagen deposition in obese individuals.
... cDNA was synthesized using a cDNA synthesis kit (Yekta Tajhiz, Tehran, Iran). Then genes of interest were amplified using the master mix SYBR green kit (Amplicon, Denmark) and specific primers (Table 1) [12,[14][15][16][17] in a Mic qPCR Cycler. The selected primers in this study were blasted by Primer Blast Software. ...
Aging is associated with an increase in oxidative stress, which damages organs such as the kidney. Trehalose has abundant beneficial activities including antioxidative effects. This study aimed to investigate the effects of trehalose on several antioxidant parameters of the aged kidney. Wistar rats were divided into three groups: young (4 months), aged (24 months), and aged-trehalose. The third group was treated with 2% trehalose for one month. The expression of target genes and enzyme activities in the kidney of the animals were evaluated by quantitative polymerase chain reaction (qPCR) and enzyme colorimetric procedures, respectively. Protein levels of NFE2L2 showed a 50% reduction in aged rats compared to young rats (P<0.001), which was restored by trehalose intervention. In addition, the activity and mRNA levels of catalase (CAT) increased in aged rats while treatment with trehalose reversed this trend. On the other hand, superoxide dismutase (SOD) activity was reduced in the kidneys of aged rats but was not affected by trehalose intervention .It is concluded that trehalose supplementation alleviates the antioxidant system impairments in the kidneys of aged rats. However, further investigations are needed to thoroughly describe the antioxidative impacts of trehalose on the kidneys during aging.
... Adiponectin (APN) is an adipokine with pleiotropic cardioprotective effects [10,11] and has shown great potential in improving the myocardial environment after AMI. APN activates the adenosine monophosphate-activated protein kinase (AMPK)-dependent signaling pathway [12] to exert its cardioprotective effects [13], including the prevention of myocardial ischemic-reperfusion injury [14]. APN supplementation might protect the heart from the development of systolic dysfunction following ischemic myocardial infarction through its ability to suppress cardiac hypertrophy and interstitial fibrosis, increase capillary density and protect against cardiomyocyte apoptosis [15]. ...
Poor viability of transplanted mesenchymal stem cells (MSCs) within the ischemic heart has limited their therapeutic potential for cardiac repair. We have previously shown that adiponectin (APN) treatment inhibits MSCs apoptosis under ischemic conditions in vitro. In this study, we investigated whether APN promoted the survival of MSCs in vivo and further contributed to cardiac repair in a rat model of acute myocardial infarction (AMI) by activating the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Rats were randomized into six groups: the sham, AMI control, and four other groups that were subjected to AMI followed by treatment with MSCs, APN, APN + MSCs, and APN + MSCs + AMPK inhibitor, respectively. The engraftment and survival of MSCs were detected using both immunofluorescence staining and qPCR. Cardiac function was assessed using echocardiography and left heart catheterization. H&E staining and immunohistochemical staining for MHC-II and CD206 were performed to assess the infiltration of inflammatory cells. Immunostaining for the smooth muscle cell marker α-smooth-muscle actin (α-SMA) and endothelial cell marker CD31 was performed to assess arteriogenesis and angiogenesis. APN treatment significantly enhanced the engraftment and survival rate of transplanted MSCs and further improved cardiac function and led to reduced infarct size compared with MSCs treatment alone at 4 weeks after AMI. Combined administration of APN and MSCs noticeably suppressed the inflammatory response by specifically promoting the shift of infiltrated macrophages to an less-inflammatory phenotype. Combined administration of APN and MSCs also significantly inhibited cardiomyocyte apoptosis and increased arteriogenesis and angiogenesis in the peri-infarct myocardium compared with MSCs transplantation alone. These protective effects of APN were associated with AMPK phosphorylation and were partially reversed by AMPK pathway inhibitors. Our results are the first to show that APN is able to effectively improve the survival and therapeutic efficacy of transplanted MSCs after AMI through AMPK activation. APN has the potential to be utilized for stem cell-based heart repair after AMI.
... Zhu et al. [250] found that IPostC, in primary rat ventricular cardiomyocytes exposed to H/R, is able to reduce H/R-induced cell damage, with concomitant enhancement of STAT3 phosphorylation S727 but not at Y705. These authors were interested in the involvement of 5' Adenosine Monophosphate-activated protein kinase (AMPK) in IPostC and they found that STAT3 phosphorylation was not affected by the inhibition of AMPK, as well as the protective effects of IPostC were not abrogated, suggesting that IPostC in vitro relies on STAT3 and this is independent of AMPK signaling. ...
... These authors were interested in the involvement of 5' Adenosine Monophosphate-activated protein kinase (AMPK) in IPostC and they found that STAT3 phosphorylation was not affected by the inhibition of AMPK, as well as the protective effects of IPostC were not abrogated, suggesting that IPostC in vitro relies on STAT3 and this is independent of AMPK signaling. In vivo model of MI achieved with LAD occlusion gave similar results with IPostC, increasing the level of S727 but not Y705 phosphorylation of STAT3 [250]. Moreover, they compared IPostC to pharmacological postconditioning with Adiponectin and they found that while IPostC induced STAT3 activation by S727 phosphorylation, the latter activated/phosphorylated STAT3 in Y705, supporting the difference between ischemic and pharmacological conditioning. ...
... Moreover, they compared IPostC to pharmacological postconditioning with Adiponectin and they found that while IPostC induced STAT3 activation by S727 phosphorylation, the latter activated/phosphorylated STAT3 in Y705, supporting the difference between ischemic and pharmacological conditioning. Interestingly, the combination of IPostC and Adiponectin conditioning provided additional protection in comparison with the conditioning alone, and promoted the phosphorylation of both sites of STAT3 [250]. This suggests that the integration of canonical pathway of STAT3 (transcription of antioxidant and anti-apoptotic genes) with the mitochondrial pathway (reduction of ROS production, mPTPs opening prevention, optimization of complex I activity) is able to provide maximal cardioprotection in vivo. ...
Ischemia–reperfusion injury (IRI) is one of the biggest challenges for cardiovascular researchers given the huge death toll caused by myocardial ischemic disease. Cardioprotective conditioning strategies, namely pre- and post-conditioning maneuvers, represent the most important strategies for stimulating pro-survival pathways essential to preserve cardiac health. Conditioning maneuvers have proved to be fundamental for the knowledge of the molecular basis of both IRI and cardioprotection. Among this evidence, the importance of signal transducer and activator of transcription 3 (STAT3) emerged. STAT3 is not only a transcription factor but also exhibits non-genomic pro-survival functions preserving mitochondrial function from IRI. Indeed, STAT3 is emerging as an influencer of mitochondrial function to explain the cardioprotection phenomena. Studying cardioprotection, STAT3 proved to be crucial as an element of the survivor activating factor enhancement (SAFE) pathway, which converges on mitochondria and influences their function by cross-talking with other cardioprotective pathways. Clearly there are still some functional properties of STAT3 to be discovered. Therefore, in this review, we highlight the evidence that places STAT3 as a promoter of the metabolic network. In particular, we focus on the possible interactions of STAT3 with processes aimed at maintaining mitochondrial functions, including the regulation of the electron transport chain, the production of reactive oxygen species, the homeostasis of Ca²⁺ and the inhibition of opening of mitochondrial permeability transition pore. Then we consider the role of STAT3 and the parallels between STA3/STAT5 in cardioprotection by conditioning, giving emphasis to the human heart and confounders.
... Oxidative stress, an imbalanced condition, irritated by massive burst production of reactive oxygen species (ROS) in the absence of sufficient antioxidant reservation during myocardial reperfusion has been substantiated to play an imperative role in causing and aggravating I/R injury. Oxidative stress also acts as a signal to induce apoptosis, autophagy and necrosis during acute ischemia-reperfusion injury [8][9][10][11][12]. Among all these manners of cell death, apoptosis appears to be an inseparable part in the elimination of invalid cells and it's evidenced that the reduction in the expression of apoptosis-inducing Bax gene is beneficial to myocardial I/R injury [13]. ...
Background:
Administration of propofol, an intravenous anesthetic with antioxidant property, immediately at the onset of post-ischemic reperfusion (propofol postconditioning, P-PostC) has been shown to confer cardioprotection against ischemia-reperfusion injury, while the underlying mechanism remains incompletely understood. The FoxO transcription factors are reported to play critical roles in activating cardiomyocyte survival signaling throughout the process of cellular injuries induced by oxidative stress and are also involved in hypoxic postconditioning mediated neuroprotection, however, the role of FoxO in postconditioning mediated protection in the heart and in particular in high glucose condition is unknown.
Methods:
Rat heart-derived H9c2 cells were exposed to high glucose (HG) for 48 h (h), then subjected to hypoxia/reoxygenation (H/R, composed of 8 h of hypoxia followed by 12 h of reoxygenation) in the absence or presence of postconditioning with various concentrations of propofol (P-PostC) at the onset of reoxygenation. After having identified the optical concentration of propofol, H9c2 cells were subjected to H/R and P-PostC in the absence or presence of FoxO1 or FoxO3a gene silencing to explore their roles in P-PostC mediated protection against apoptotic and autophagic cell deaths under hyperglycemia.
Results:
The results showed that HG with or without H/R decreased cell viability, increased lactate dehydrogenase (LDH) leakage and the production of reactive oxygen species (ROS) in H9c2 cells, all of which were significantly reversed by propofol (P-PostC), especially at the concentration of 25 µmol/L (P25) (all P < 0.05, NC vs. HG; HG vs. HG + HR; HG + HR + P12.5 or HG + HR + P25 or HG + HR + P50 vs. HG + HR). Moreover, we found that propofol (P25) decreased H9c2 cells apoptosis and autophagy that were concomitant with increased FoxO1 and FoxO3a expression (all P < 0.05, HG + HR + P25 vs. HG + HR). The protective effects of propofol (P25) against H/R injury were reversed by silencing FoxO1 or FoxO3a (all P < 0.05, HG + HR + P25 vs. HG + HR + P25 + siRNA-1 or HG + HR + P25 + siRNA-5).
Conclusion:
It is concluded that propofol postconditioning attenuated H9c2 cardiac cells apoptosis and autophagy induced by H/R injury through upregulating FoxO1 and FoxO3a under hyperglycemia.
... IPo was established by the group of Vinten-Johansen (Zhao et al., 2003) who first reported 3 cycles of 30 s reperfusion/30 s reocclusion immediately at the onset of reperfusion after 60 min of LAD occlusion. A recent study showed that 3 cycles of 10 s of reocclusion and 10 s of reperfusion at the onset of reperfusion conferred cardioprotection by reducing ROS production through AMPKindependent activation of STAT3 at Ser727 (Zhu et al., 2020). The myocardial protective effect of IPo also relies on regulating energy homeostasis and the expression of myocardial mitochondrial proteins . ...
Intestinal mucosal barrier dysfunction induced by myocardial ischemia reperfusion (IR) injury often leads to adverse cardiovascular outcomes after myocardial infarction. Early detection and prevention of remote intestinal injury following myocardial IR may help to estimate and improve prognosis after acute myocardial infarction (AMI). This study investigated the protective effect of myocardial ischemic postconditioning (IPo) on intestinal barrier injury induced by myocardial IR and the underlying cellular signaling mechanisms with a focus on the DJ-1. Adult SD rats were subjected to unilateral myocardial IR with or without ischemic postconditioning. After 30 min of ischemia and 120 min of reperfusion, heart tissue, intestine, and blood were collected for subsequent examination. The outcome measures were (i) intestinal histopathology, (ii) intestinal barrier function and inflammatory responses, (iii) apoptosis and oxidative stress, and (iv) cellular signaling changes. IPo significantly attenuated intestinal injury induced by myocardial IR. Furthermore, IPo significantly increased DJ-1, nuclear Nrf2, NQO1, and HO-1 expression in the intestine and inhibited IR-induced apoptosis and oxidative stress. The protective effect of IPo was abolished by the knockdown of DJ-1. Conversely, the overexpression of DJ-1 provided a protective effect similar to that of IPo. Our data indicate that IPo protects the intestine against myocardial IR, which is likely mediated by the upregulation of DJ-1/Nrf2 pathway.
... Adiponectin treatment is shown to induce the activation of ceramidase (CDase) and subsequently prevents apoptosis of isolated ventricular cardiomyocytes from obese mice through the degradation of ceramides [60]. Adiponectin has been shown to involve myocardial ischemic postconditioning (IPo)-mediated cardioprotection against myocardial ischemia-reperfusion (IR) injury in rodents via both AMPK-dependent nuclear and AMPK-independent mitochondrial signal transducer and activator of transcription (STAT)3 activation [61]. Adipo KO mice exhibited enhanced myocardial apoptosis, infract size, levels of nitric oxide (NO), inducible nitric oxide synthase (iNOS), superoxide, and their cytotoxic reaction products, peroxynitrite, in cardiac tissues [62]. ...
According to the World Health Organization, metabolic syndrome (MetS) can be defined as a pathological condition characterized by abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. The incidence of MetS keeps rising, as at least 35% of the USA population suffers from MetS. One of the worst comorbidities of metabolic syndrome are cardiovascular diseases that significantly amplifies the mortality associated with this syndrome. There is an urgent need to understand the pathophysiology of MetS to find novel diagnosis, treatment and management to mitigate the MetS and associated complications. Altered circulatory adiponectin levels have been implicated in MetS. Adiponectin has numerous biologic functions including antioxidative, anti-nitrative, anti-inflammatory, and cardioprotective effects. Being a pleiotropic hormone of multiple tissues, tissue-specific key signaling pathways of adiponectin will help finding specific target/s to blunt the pathophysiology of metabolic syndrome and associated disorders. The purpose of this review is to elucidate tissue-specific signaling pathways of adiponectin and possibly identify potential therapeutic targets for MetS as well as to evaluate the potential of adiponectin as a biomarker/therapeutic option in MetS.
