Abstract 339: Vasonatrin Peptide Attenuates Myocardial Ischemia/Reperfusion Injury in Diabetic Rats through PKG-Mediated Inhibition of Endoplasmic Reticulum Stress

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Haifeng Zhang ◽  
Liming Yu ◽  
Zhenwei Shi ◽  
Weifeng Lv ◽  
Ru Tie ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Heart Disease ◽  
Myocardial Ischemia ◽  
Ischemic Heart Disease ◽  
Er Stress ◽  
Natriuretic Peptide ◽  
Ischemia Reperfusion ◽  
Diabetic Rats ◽  
Diabetic Patients ◽  
Myocardial Ischemia Reperfusion

Diabetes mellitus (DM) increases morbidity/mortality of ischemic heart disease (IHD). Although atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) reduce the myocardial ischemia/reperfusion (MI/R) damage in non-diabetic rats, whether vasonatrin peptide (VNP), the artificial synthetic chimera of ANP and CNP, confers cardioprotective effect against acute MI/R injury, especially in diabetic patients, is still unclear. This study aimed to investigate the effects of VNP on MI/R injury in diabetic rats and the involved mechanisms. The high-fat diet-fed streptozotocin (HFD-STZ) induced diabetic rats were subjected to MI/R (30 min/4 h). VNP treatment (100 µg/kg, i.v., 10 min before R) significantly improved ± LV d P /dt max [(3242 ± 103) and -(2731 ± 79) mm Hg/s vs. (2936 ± 90) and -(2422 ± 83) mm Hg/s in DM group] and LVSP and reduced LVEDP, and reduced infarct size [(43.3 ± 3.6) % vs (53.5 ± 2.8) %], apoptosis index [(36.0 ± 2.1) % vs. (45.7 ± 3.5) %], caspase-3 activity, serum CK and LDH levels (n=8, P <0.05). Moreover, VNP inhibited endoplasmic reticulum (ER) stress by suppressing GRP78 and CHOP (n=3, P <0.05), and consequently increased the antiapoptotic protein Akt and ERK1/2 expression and phosphorylation levels ( P <0.05). These effects were mimicked by 8-Br-cGMP (1 mg/kg, i.p., 20 min before R), a cGMP analogue, whereas inhibited by KT-5823 (0.5 mg/kg, i.p.), the selective inhibitor of PKG (both P <0.05). In addition, pretreated DM rats with TUDCA (50 mg/kg, i.p.), a specific inhibitor of ER stress, couldn’t further promote the VNP’s cardioprotective effect ( P >0.05). In vitro study was performed using H9c2 cardiomyocytes subjected to hypoxia/reoxygenation (H/R, 3 h/6 h) and incubated with or without VNP (10 -8 mol/L). Gene knockdown of PKG1α with siRNA blunted VNP’s inhibition of ER stress and apoptosis (n=6, P <0.05), while overexpression of PKG1α resulted in significant decreased ER stress and apoptosis (n=6, P <0.01). In conclusion, VNP protects diabetic heart against MI/R injury by inhibiting ER stress via cGMP-PKG signaling pathway. These results suggest that VNP may have potential therapeutic value for the diabetic patients with ischemic heart disease.

Vasonatrin peptide attenuates myocardial ischemia-reperfusion injury in diabetic rats and underlying mechanisms

2015 ◽  
Vol 308 (4) ◽  
pp. H281-H290 ◽  
Author(s):  
Zhenwei Shi ◽  
Feng Fu ◽  
Liming Yu ◽  
Wenjuan Xing ◽  
Feifei Su ◽  
...  
Keyword(s):  
Heart Disease ◽  
Myocardial Ischemia ◽  
Er Stress ◽  
Reperfusion Injury ◽  
Natriuretic Peptide ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Diabetic Rats ◽  
Diabetic Patients ◽  
Myocardial Ischemia Reperfusion

Diabetes mellitus increases morbidity/mortality of ischemic heart disease. Although atrial natriuretic peptide and C-type natriuretic peptide reduce the myocardial ischemia-reperfusion damage in nondiabetic rats, whether vasonatrin peptide (VNP), the artificial synthetic chimera of atrial natriuretic peptide and C-type natriuretic peptide, confers cardioprotective effects against ischemia-reperfusion injury, especially in diabetic patients, is still unclear. This study was designed to investigate the effects of VNP on ischemia-reperfusion injury in diabetic rats and to further elucidate its mechanisms. The high-fat diet-fed streptozotocin-induced diabetic Sprague-Dawley rats were subjected to ischemia-reperfusion operation. VNP treatment (100 μg/kg iv, 10 min before reperfusion) significantly improved the instantaneous first derivation of left ventricle pressure (±LV dP/d tmax) and LV systolic pressure and reduced LV end-diastolic pressure, apoptosis index, caspase-3 activity, plasma creatine kinase (CK), and lactate dehydrogenase (LDH) activities. Moreover, VNP inhibited endoplasmic reticulum (ER) stress by suppressing glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP). These effects were mimicked by 8-bromine-cyclic guanosinemonophosphate (8-Br-cGMP), a cGMP analog, whereas they were inhibited by KT-5823, the selective inhibitor of PKG. In addition, pretreatment with tauroursodeoxycholic acid (TUDCA), a specific inhibitor of ER stress, could not further promote the VNP's cardioprotective effect in diabetic rats. In vitro H9c2 cardiomyocytes were subjected to hypoxia/reoxygenation and incubated with or without VNP (10−8 mol/l). Gene knockdown of PKG1α with siRNA blunted VNP inhibition of ER stress and apoptosis, while overexpression of PKG1α resulted in significant decreased ER stress and apoptosis. VNP protects the diabetic heart against ischemia-reperfusion injury by inhibiting ER stress via the cGMP-PKG signaling pathway. These results suggest that VNP may have potential therapeutic value for the diabetic patients with ischemic heart disease.

scholarly journals iPLA2β Contributes to ER Stress-Induced Apoptosis during Myocardial Ischemia/Reperfusion Injury

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1446
Author(s):  
Tingting Jin ◽  
Jun Lin ◽  
Yingchao Gong ◽  
Xukun Bi ◽  
Shasha Hu ◽  
...  
Keyword(s):  
Cell Death ◽  
Heart Disease ◽  
Myocardial Ischemia ◽  
Ischemic Heart Disease ◽  
Er Stress ◽  
Ischemia Reperfusion ◽  
Myocardial Ischemia Reperfusion ◽  
Induced Apoptosis

Both calcium-independent phospholipase A2 beta (iPLA2β) and endoplasmic reticulum (ER) stress regulate important pathophysiological processes including inflammation, calcium homeostasis and apoptosis. However, their roles in ischemic heart disease are poorly understood. Here, we show that the expression of iPLA2β is increased during myocardial ischemia/reperfusion (I/R) injury, concomitant with the induction of ER stress and the upregulation of cell death. We further show that the levels of iPLA2β in serum collected from acute myocardial infarction (AMI) patients and in samples collected from both in vivo and in vitro I/R injury models are significantly elevated. Further, iPLA2β knockout mice and siRNA mediated iPLA2β knockdown are employed to evaluate the ER stress and cell apoptosis during I/R injury. Additionally, cell surface protein biotinylation and immunofluorescence assays are used to trace and locate iPLA2β. Our data demonstrate the increase of iPLA2β augments ER stress and enhances cardiomyocyte apoptosis during I/R injury in vitro and in vivo. Inhibition of iPLA2β ameliorates ER stress and decreases cell death. Mechanistically, iPLA2β promotes ER stress and apoptosis by translocating to ER upon myocardial I/R injury. Together, our study suggests iPLA2β contributes to ER stress-induced apoptosis during myocardial I/R injury, which may serve as a potential therapeutic target against ischemic heart disease.

Abstract 104: Vasonatrin Peptide Inhibits Endoplasmic Reticulum Stress and Attenuates Myocardial Ischemia/reperfusion Injury in Diabetic Rats

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Haifeng Zhang ◽  
Wenjuan Xing ◽  
Feng Gao
Keyword(s):  
Endoplasmic Reticulum ◽  
Myocardial Ischemia ◽  
Er Stress ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Diabetic Rats ◽  
H9c2 Cardiomyocytes ◽  
Myocardial Ischemia Reperfusion ◽  
Underlying Mechanisms

Aims: Diabetes mellitus (DM) increases morbidity/mortality of ischemic heart disease. Although the ability of the natriuretic peptides to modulate cardiac function and cell proliferation has been recognized, their effects on myocardial ischemia/reperfusion (MI/R) injury is still unclear. This study was to investigate the effects of the artificial synthetic natriuretic peptide — vasonatrin peptide (VNP) on MI/R injury in diabetic rats, and underlying mechanisms. Method: The high-fat diet-fed streptozotocin induced diabetic rats were subjected to MI/R (30 min/4 h) and VNP treatment (100 μg/kg, i.v., 10 min before R). In vitro study was performed using H9c2 cardiomyocytes subjected to hypoxia/reoxygenation (H/R, 3 h/6 h) and incubated with or without VNP (10 -8 mol/L). Result: The diabetic state aggravated MI/R injury and showed more severe myocardial functional impairment than normal state. VNP treatment (100 μg/kg, i.v., 10 min before R) significantly improved ± LV d P /dt max and LVSP, and decreased infarct size, apoptosis index, caspase-3 activity, serum CK and LDH levels (n=8, P <0.05). Moreover, VNP inhibited endoplasmic reticulum (ER) stress by suppressing GRP78 and CHOP, and consequently increased Akt and ERK1/2 expression and phosphorylation levels (n=3, P <0.05). These effects were mimicked by 8-Br-cGMP (1 mg/kg, i.p., 20 min before R), a cGMP analogue, whereas inhibited by KT-5823 (0.5 mg/kg, i.p.), the selective inhibitor of PKG ( P <0.05). Pretreated DM rats with TUDCA (50 mg/kg, i.p.), an inhibitor of ER stress, couldn’t further promote the VNP’s cardioprotective effect. Additionally, gene knockdown of PKG1α with siRNA blunted VNP’s inhibition of ER stress and apoptosis, while overexpression of PKG1α resulted in significant decreased ER stress and apoptosis in H/R H9c2 cardiomyocytes (n=6, P <0.05). Conclusion: We demonstrated that VNP protects diabetic heart against MI/R injury by inhibiting ER stress via cGMP-PKG signaling pathway.

Repeated intermittent stress exacerbates myocardial ischemia-reperfusion injury

1998 ◽  
Vol 274 (2) ◽  
pp. R470-R475 ◽  
Author(s):  
Deborah A. Scheuer ◽  
Steven W. Mifflin
Keyword(s):  
Heart Disease ◽  
Myocardial Ischemia ◽  
Ischemic Heart Disease ◽  
Infarct Size ◽  
Chronic Stress ◽  
Restraint Stress ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Chronic stress in humans has been correlated with increased risk for ischemic heart disease. Thus experiments were conducted to determine if repeated intermittent restraint stress increased infarct size in a rat model of myocardial ischemia-reperfusion injury. Male Sprague-Dawley rats were subjected to no stress (control) or to daily restraint stress for 1–1.5 h for 8–14 days (stress protocol A) or for 2 h daily for 11 or 12 days (stress protocol B). Myocardial ischemia-reperfusion (30-min ischemia, 3-h reperfusion) was performed in anesthetized rats. Average baseline arterial pressures were 111 ± 4, 120 ± 10, and 125 ± 7 mmHg in the control, stress protocol A, and stress protocol B groups, respectively. Infarct size (%area at risk) was significantly larger in both groups of stressed rats compared with control rats (58 ± 5, 78 ± 2, and 79 ± 3% in the control, stress protocol A, and stress protocol B groups, respectively). During ischemia or early reperfusion, zero of eight control, two of six protocol A stress, and two of five protocol B stress rats had at least one period of severe arrhythmia. Therefore, these results provide experimental evidence corroborating correlative studies in humans that link chronic stress with increased morbidity and mortality from ischemic heart disease.

scholarly journals Novel Insight into the Role of Endoplasmic Reticulum Stress in the Pathogenesis of Myocardial Ischemia-Reperfusion Injury

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Hang Zhu ◽  
Hao Zhou
Keyword(s):  
Endoplasmic Reticulum ◽  
Myocardial Ischemia ◽  
Er Stress ◽  
Stress Responses ◽  
Molecular Mechanisms ◽  
Defense Mechanism ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Myocardial Ischemia Reperfusion ◽  
Er Homeostasis

Impaired function of the endoplasmic reticulum (ER) is followed by evolutionarily conserved cell stress responses, which are employed by cells, including cardiomyocytes, to maintain and/or restore ER homeostasis. ER stress activates the unfolded protein response (UPR) to degrade and remove abnormal proteins from the ER lumen. Although the UPR is an intracellular defense mechanism to sustain cardiomyocyte viability and heart function, excessive activation initiates ER-dependent cardiomyocyte apoptosis. Myocardial ischemia/reperfusion (I/R) injury is a pathological process occurring during or after revascularization of ischemic myocardium. Several molecular mechanisms contribute to the pathogenesis of cardiac I/R injury. Due to the dual protective/degradative effects of ER stress on cardiomyocyte viability and function, it is of interest to understand the basic concepts, regulatory signals, and molecular processes involved in ER stress following myocardial I/R injury. In this review, therefore, we present recent findings related to the novel components of ER stress activation. The complex effects of ER stress and whether they mitigate or exacerbate myocardial I/R injury are summarized to serve as the basis for research into potential therapies for cardioprotection through control of ER homeostasis.

Abstract 343: Activation of ROR-α, but not ROR-β or ROR-γ, Protects against Myocardial Ischemia/Reperfusion Injury

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Jun Pu ◽  
Ben He ◽  
Erhe Gao ◽  
Xinliang Ma ◽  
Yajing Wang
Keyword(s):  
Endoplasmic Reticulum ◽  
Myocardial Ischemia ◽  
Cardiac Function ◽  
Infarct Size ◽  
Er Stress ◽  
Ischemia Reperfusion ◽  
Specific Gene ◽  
Mitochondrial Impairment ◽  
Nitrative Stress ◽  
Myocardial Ischemia Reperfusion

Objectives: The RAR-related orphan receptors (RORs) are members of the nuclear receptor superfamily that play a pivotal role in many physiological processes, including regulation of the circadian rhythm, development, metabolism and immune function. Three different but highly homologous ROR isoforms, ROR-α, -β, and -γ, have been discovered separately. However, the functional roles of RORs in the heart have never been investigated. We investigate the role of RORs in the pathophysiology of acute myocardial ischemia/ reperfusion (MI/R) injury. Methods and Results: The endogenous RORα, but not RORβ or RORγ, was significantly upregulated after MI/R. Synthetic ROR agonists SR1078 and SR3335 reduced myocardial infarction and improved contractile function after MI/R. Mechanistically, ROR activation inhibited endoplasmic reticulum (ER) stress, attenuated mitochondrial impairment, reduced cardiomyocyte apoptosis, and inhibited MI/R-induced autophagy dysfunction. Moreover, ROR activation inhibited MI/R-induced oxidative stress and nitrative stress. The aforementioned cardioprotective effects of ROR agonists were impaired in the setting of cardiac-specific gene silencing of RORα, but not RORβ or RORγ subtype. In contrast, adenovirus-mediated cardiac RORα overexpression, but not RORβ or RORγ overexpression, decreased myocardial infarct size and improved cardiac function through attenuating oxidative/nitrative stress and inhibiting ER stress, mitochondrial impairment, and autophagy dysfunction. Finally, RORα sg/sg mice (loss-of-function mutation in RORα), but not RORβ-null or RORγ-null mice, increased MI/R injury (greater apoptosis, larger infarct size, and poor cardiac function), exacerbated MI/R-induced oxidative/nitrative stress, and aggravated endoplasmic-reticulum stress, mitochondrial dysfunction, and autophagy dysfunction. Conclusion: Our study provides the first direct evidence that RORα acts as a novel endogenous cardioprotective receptor against myocardial injury. RORα, but not RORβ or RORγ, is a novel cardiac protective receptor against MI/R injury, supporting for the drug development strategies specifically targeting RORα for the treatment of ischemic heart disease.

scholarly journals Activation of endoplasmic reticulum stress response during the development of ischemic heart disease

2006 ◽  
Vol 291 (3) ◽  
pp. H1411-H1420 ◽  
Author(s):  
Asim Azfer ◽  
Jianli Niu ◽  
Linda M. Rogers ◽  
Frances M. Adamski ◽  
Pappachan E. Kolattukudy
Keyword(s):  
Endoplasmic Reticulum ◽  
Heart Disease ◽  
Stress Response ◽  
Transgenic Mice ◽  
Ischemic Heart Disease ◽  
Er Stress ◽  
Stress Proteins ◽  
Gene Array ◽  
Ischemic Heart ◽  
Endoplasmic Reticulum Stress Response

Endoplasmic reticulum (ER) stress has been found to be associated with neurodegenerative diseases and diabetes mellitus. Whether ER stress is involved in the development of heart disease is not known. Cardiac-specific expression of monocyte chemoattractant protein-1 (MCP-1) in mice causes the development of ischemic heart disease. Here we report that microarray analysis of gene expression changes in the heart of these transgenic mice revealed that a cluster of ER stress-related genes was transcriptionally activated in the heart during the development of ischemic heart disease. The gene array results were verified by quantitative real-time PCR that showed highly elevated transcript levels of genes involved in unfolded protein response such as ER and cytoplasmic chaperones, oxidoreductases, protein disulfide isomerase (PDI) family, and ER-associated degradation system such as ubiquitin. Immunoblot analysis confirmed the expression of chaperones, PDI, and ubiquitin. Immunohistochemical analyses showed that ER stress proteins were associated mainly with the degenerating cardiomyocytes. A novel ubiquitin fold modifier (Ufm1) that has not been previously associated with ER stress and not found to be induced under any condition was also found to be upregulated in the hearts of MCP mice (transgenic mice that express MCP-1 specifically in the heart). The present results strongly suggest that activation of ER stress response is involved in the development of ischemic heart disease in this murine model.

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