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.

scholarly journals Naringenin Attenuates Myocardial Ischemia-Reperfusion Injury via cGMP-PKGIα Signaling and In Vivo and In Vitro Studies

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Li-Ming Yu ◽  
Xue Dong ◽  
Jian Zhang ◽  
Zhi Li ◽  
Xiao-Dong Xue ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Ischemia ◽  
Er Stress ◽  
Ischemia Reperfusion Injury ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Guanosine Monophosphate ◽  
Myocardial Ischemia Reperfusion

Endoplasmic reticulum (ER) stress and oxidative stress contribute greatly to myocardial ischemia-reperfusion (MI/R) injury. Naringenin, a flavonoid derived from the citrus genus, exerts cardioprotective effects. However, the effects of naringenin on ER stress as well as oxidative stress under MI/R condition and the detailed mechanisms remain poorly defined. This study investigated the protective effect of naringenin on MI/R-injured heart with a focus on cyclic guanosine monophosphate- (cGMP-) dependent protein kinase (PKG) signaling. Sprague-Dawley rats were treated with naringenin (50 mg/kg/d) and subjected to MI/R surgery with or without KT5823 (2 mg/kg, a selective inhibitor of PKG) cotreatment. Cellular experiment was conducted on H9c2 cardiomyoblasts subjected to simulated ischemia-reperfusion treatment. Before the treatment, the cells were incubated with naringenin (80 μmol/L). PKGIα siRNA was employed to inhibit PKG signaling. Our in vivo and in vitro data showed that naringenin effectively improved heart function while it attenuated myocardial apoptosis and infarction. Furthermore, pretreatment with naringenin suppressed MI/R-induced oxidative stress as well as ER stress as evidenced by decreased superoxide generation, myocardial MDA level, gp91phox expression, and phosphorylation of PERK, IRE1α, and EIF2α as well as reduced ATF6 and CHOP. Importantly, naringenin significantly activated myocardial cGMP-PKGIα signaling while inhibition of PKG signaling with KT5823 (in vivo) or siRNA (in vitro) not only abolished these actions but also blunted naringenin’s inhibitory effects against oxidative stress and ER stress. In summary, our study demonstrates that naringenin treatment protects against MI/R injury by reducing oxidative stress and ER stress via cGMP-PKGIα signaling. Its cardioprotective effect deserves further clinical study.

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.

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.

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 423: Proteasome Priming by Protein Kinase G Protects Against Myocardial Ischemia-reperfusion Injury

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Xuejun Wang ◽  
Erin J Terpstra ◽  
Eduardo Callegari ◽  
Chengjun Hu ◽  
Hanming Zhang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Myocardial Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Underlying Mechanism ◽  
26S Proteasome ◽  
Transgenic Mouse Line ◽  
Pde5 Inhibition ◽  
Myocardial Ischemia Reperfusion

Cardiac proteasome functional insufficiency is implicated in a large subset of heart disease and has been experimentally demonstrated to play an essential role in cardiac proteotoxicity, including desmin-related cardiomyopathy and myocardial ischemia-reperfusion (I-R) injury. Pharmacological inhibition of phosphodiesterase 5 (PDE5) via sildenafil for example, which can stabilize cGMP and thereby increase cGMP-dependent protein kinase (PKG) activity, is consistently reported to protect against I-R injury; however, the underlying mechanism is not fully understood. We have recently discovered that PKG activation enhances proteasomal degradation of misfolded proteins (Ranek, et al. Circulation 2013), prompting us to hypothesize that proteasome-priming may contribute to cardioprotection-induced by PDE5 inhibition. Here we used a cardiomyocyte-restricted proteasome inhibition transgenic mouse line (Tg) and non-Tg (Ntg) littermates to interrogate the action of sildenafil on I-R injury created by left anterior descending artery (LAD) ligation (30 min) and release (24 hr). Sildenafil was administered 30 min before LAD ligation. Results showed that (1) the 26S proteasome activity of the Ntg I-R hearts was significantly elevated by sildenafil but this elevation was blocked in the Tg line; (2) the infarct size reduction by sildenafil treatment in Ntg mice was completely abolished in the Tg mice with the same treatment; and (3) systolic and diastolic function impairment after I/R was markedly attenuated in sildenafil-treated Ntg mice, but not in the sildenafil-treated Tg mice. Additionally, immunoprecipitation assays show that PKG interacted with the proteasome in cultured cardiomyocytes, and this interaction appeared to be augmented by sildenafil treatment. Moreover, in vitro incubation of active PKG with purified human 26S proteasomes increased proteasome peptidase activities and the phosphorylation at specific serine residues of a 19S proteasome subunit as revealed by “gel-free” nano-LC-MS/MS. We conclude that active PKG directly interacts with, phosphorylates, and increases the activities of, the proteasome and that proteasome priming mediates to cardioprotection of PDE5 inhibition against I-R injury.

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