scholarly journals Therapeutic activity of sarpogrelate and dopamine D2 receptor agonists on cardiovascular and renal systems in rats with alloxan-induced diabetes

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Mohammed Ahmed Fouad Shalaby ◽  
Hekma A. Abd El Latif ◽  
Mohamed El Yamani ◽  
May Ahmed Galal ◽  
Sherifa Kamal ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Myocardial Injury ◽  
Troponin I ◽  
Staining Method ◽  
Myocardial Infarct ◽  
Myocardial Infarct Size ◽  
Blood Concentrations ◽  
Receptor Agonists ◽  
Long Term Treatment ◽  
Kidney Hypertrophy

Abstract Background Dopamine D2 receptor agonists, bromocriptine and cabergoline, are notable medications in the treatment of Parkinsonism, hyperprolactinemia, and hyperglycemia. An affiliation was found between the initiation of myocardial injury ailment and long term treatment with dopamine D2 agonist drugs identified with the partial activation of 5-hydroxytryptamine receptor 2 A (5-HT2A). The investigation aimed to examine the activity of sarpogrelate (a 5-HT2A receptor blocker) in reducing myocardial injury prompted by extended haul utilisation of D2 receptor agonists in rats with alloxan-induced diabetes. Methods Both bromocriptine and cabergoline were managed independently and combined with sarpogrelate for about a month in diabetic nephropathy rats. Both tail-cuff blood pressure and the BGL were recorded weekly. For all animals, the kidney hypertrophy index, serum creatinine, blood urea nitrogen, alanine transaminase, and aspartate transaminase levels were measured after one month of treatment. The severity of the cardiac injury was assessed by the estimation of lactate dehydrogenase-1 (LDH-1), cardiac troponin I, and tumor necrosis factor alpha 1 (TNF1). The triphenyltetrazolium chloride (TTC) staining method was used to determine the experimental myocardial infarction (MI) size. Results Bromocriptine and cabergoline created a significant reduction in BGL, BP, and kidney hypertrophy index in diabetic nephropathy rats. Administration of bromocriptine and cabergoline, alone, or in combination with sarpogrelate fundamentally diminished the blood concentrations of alkaline phosphatase (ALP), Aspartate aminotransferase (AST), urea, and creatinine. Bromocriptine and cabergoline alone showed a noteworthy increase in the LDH-1, Troponin I, and TNF1 levels in the serum (p < 0.05). Paradoxically, utilising bromocriptine or cabergoline with sarpogrelate treatment altogether decreased the levels of the myocardial biomarkers in the serum. A mix of bromocriptine or cabergoline with sarpogrelate diminished the level of the myocardial infarct size in the heart assessed through the TTC staining method. Conclusions The examination demonstrated that the combined use of sarpogrelate with bromocriptine or cabergoline decreased the potential adverse effects of these two drugs on the myocardial tissues.

scholarly journals Therapeutic activity of sarpogrelate, and dopamine D2 receptor agonists on cardiovascular and renal systems in alloxan-induced diabetic rats

2020 ◽  
Author(s):  
Mohamed Fouad ◽  
Hekma A. Abd El Latif ◽  
May Galal ◽  
Mohammed El Yamani ◽  
Sherifa Hassaneen ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Myocardial Injury ◽  
Troponin I ◽  
Staining Method ◽  
Diabetic Rats ◽  
Tetrazolium Chloride ◽  
Blood Concentrations ◽  
Dopamine D2 ◽  
Long Term Treatment ◽  
Kidney Hypertrophy

Abstract Background: The investigation aims to represent the activity of sarpogrelate, a particular 5-HT (2A) receptor blocker, in reducing myocardial injury prompted by extended haul utilization of D2 agonist drugs in diabetic rats. Dopamine D2 agonists are notable medications in the treatment of Parkinsonism, hyperprolactinemia, and hyperglycemia. An affiliation showed between the enlistment of myocardial injury ailment and long term treatment with dopamine D2 agonist drugs identified with the partial initiation of 5-HT 2a receptors. Methods: Both bromocriptine and cabergoline were managed independently and combined with sarpogelate for about a month to diabetic nephropathy rats. Both tail-cuff blood pressure and BGL were recorded weekly. For all animals, kidney hypertrophy index, serum creatinine, blood urea nitrogen, alanine transaminase, and aspartate transaminase levels were measured after one month of treatment. The severity of the cardiac injury was assessed by the estimation of LDH-1, cardiac troponin I, and TNFα. Triphenyl tetrazolium chloride staining method used to determine experimental myocardial infarction (MI) size. Results: Bromocriptine and cabergoline created a significant reduction in BGL, BP, and kidney hypertrophy index in diabetic nephropathy rats. Administration of bromocriptine, cabergoline, alone, or in combination with sarbogrelate fundamentally diminished blood concentrations of ALP, AST, urea, and creatinine. Bromocriptine and cabergoline alone showed noteworthy ascending of LDH-1, Troponin I, and TNFα1 levels in the serum (p<0.05). Paradoxically, utilizing bromocriptine and cabergoline with sarpogrelate treatment altogether diminished the degree of the myocardial biomarkers in the serum. A mix of bromocriptine or cabergoline with sarpogrelate diminished the level of the myocardial infarct size in the heart assessed utilizing the TTC staining method. Conclusions: The examination exhibited that both bromocriptine and cabergoline could be utilized safely in blend with sarpogrelate for a long duration of treatment for diseases like hypertension and diabetes.

scholarly journals Therapeutic activity of sarpogrelate, and dopamine D2 receptor agonists on cardiovascular and renal systems in alloxan-induced diabetic rats

2020 ◽  
Author(s):  
Mohamed Fouad ◽  
Hekma A. Abd El Latif ◽  
May Galal ◽  
Mohammed El Yamani ◽  
Sherifa Hassaneen ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Myocardial Injury ◽  
Troponin I ◽  
Dopamine D2 Receptor ◽  
Myocardial Infarct ◽  
D2 Receptor ◽  
Myocardial Infarct Size ◽  
Duration Of Treatment ◽  
Blood Concentrations ◽  
Dopamine D2

Abstract Background Dopamine D2 agonists are notable medications in the treatment of Parkinsonism, hyperprolactinemia, and hyperglycemia. An affiliation showed between the enlistment of myocardial injury ailment and long haul treatment with dopamine D2 agonist drugs identified with the partial initiation of 5-HT 2a receptors.Methods The investigation aims to represent the activity of sarpogrelate, a particular 5-HT (2A) receptor blocker, in diminishing myocardial injury prompted by extended haul utilization of D2 agonist drugs in diabetic rodents. Both bromocriptine and cabergoline managed independently and combined with sarpogelate for about a month to diabetic nephropathy rats.Results Bromocriptine and cabergoline created a significant reduction in BGL, BP, and kidney hypertrophy index in diabetic nephropathy rats. Administration of bromocriptine, cabergoline, alone, or in combination with sarbogrelate fundamentally diminished blood concentrations of ALP, AST, urea, and creatinine. Bromocriptine and cabergoline alone showed noteworthy ascending of LDH-1, Troponin I, and TNFα1 levels in the serum (p < 0.05). Paradoxically, utilizing bromocriptine and cabergoline with sarpogrelate treatment altogether diminished the degree of the myocardial biomarkers in the serum. A mix of bromocriptine or cabergoline with sarpogrelate diminished the level of the myocardial infarct size in the heart assessed utilizing the TTC staining method.Conclusions The examination exhibited that both bromocriptine and cabergoline could be utilized securely in blend with sarpogrelate for a long duration of treatment for diseases like hypertension and diabetes.

scholarly journals The cardioprotective effect of intralipid in decreasing the ischemic insults during off-pump coronary artery revascularization

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Maha Sadek El Derh ◽  
Samar Mohamed Abdel Twab ◽  
Mohamed Elgouhary
Keyword(s):  
Coronary Artery ◽  
Cardiac Index ◽  
Reperfusion Injury ◽  
Troponin I ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Control Group ◽  
Myocardial Infarct Size ◽  
Off Pump ◽  
Coronary Artery Revascularization

Abstract Background Off pump coronary artery revascularization (OPCAB) surgeries have benefits over the conventional on pump cardiac surgery, because it avoids the trauma caused by cardiopulmonary bypass (CPB) and minimize aortic manipulation. However, some disadvantages of OPCAB include the concern of ineffective coronary revascularization. Some drugs have shown the ability to protect the myocardium in different studies, by different methods. The usage of intralipid has been shown to make a better functional recovery of the cardiac muscles and help to decrease the myocardial infarct size, it shortens the action potential time, which show polyunsaturated fatty acids diets mechanism as an antiarrhythmic drug, and are associated with low incidence of coronary artery disease. Methods We divided patients into two groups according to the randomization envelopes: intralipid group (group A) received 1.5 ml/kg intralipid 20% through central venous line after sternotomy over 1 h and during infusion, blood pressure, heart rate, and temperature were monitored all through the infusion time. Control group (group B) received normal saline 0.9% in the same volume over the same duration. Results This study showed that infusion of 1.5 ml/kg intralipid after sternotomy in off pump coronary artery revascularization given as preconditioning agent improve the myocardial ischemia reperfusion injury, decrease the need for high doses of nor adrenaline infusion after revascularization, earlier normalization in troponin levels starting 24 h after surgery and higher values of cardiac index were measured in ICU using PICCO. Conclusions This study showed the benefits of infusion of 1.5 ml/kg of intralipid after sternotomy, in preconditioning during OPCABG. Preconditioning with intralipid proved to decrease reperfusion injury in myocardium expressed by improvement in cardiac functions (EF and cardiac index) and normalization of specific cardiac marker (cardiac troponin I).

Abstract 16381: Novel Thiol-activated H2S Donors Attenuate Myocardial Ischemia/Reperfusion Injury

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Chelsea Organ ◽  
Zhen Li ◽  
Yu Zhao ◽  
Chuntao Yang ◽  
Shashi Bhushan ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Sustained Release ◽  
Murine Model ◽  
Troponin I ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Myocardial Ischemia Reperfusion

Background: Hydrogen sulfide (H2S) protects against acute myocardial ischemia/reperfusion (MI/R) injury and heart failure by ameliorating oxidative stress, improving mitochondrial function, and attenuating apoptosis. One of the major limitations of currently available H2S donors is poor pharmacokinetics profiles that result in very rapid and uncontrolled H2S release. NSHD-1 and NSHD-2 are recently developed thiol-activated H2S donors designed for sustained release of H2S upon activation by molecules containing thiol groups such as cysteine and glutathione. We hypothesized that these novel H2S donors would generate H2S for extended periods and ameliorate myocardial cell death following MI/R in an in vivo murine model. Methods and Results: C57BL6/J male mice (10-12 weeks of age) were subjected to 45 minutes of MI followed by 24 hours of R. At the time of reperfusion, animals received Vehicle (0.5% THF), NSHD-1 (50 μg/kg and 100 μg/kg), or NSHD-2 (50 μg/kg) by direct intracardiac (i.c.) injection. In addition, at 4 hours of R, plasma was collected for troponin-I measurements. In preliminary studies we observed sustained release of H2S with both of these H2S donors. Myocardial infarct size was reduced by 35% (p < 0.01 vs. Vehicle) in mice treated with NSHD-1 (100 μg/kg), 43% (p < 0.05 vs. Vehicle) in mice treated with NSHD-2 (50 μg/kg), and 54% (p < 0.01 vs. Vehicle) in mice treated with NSHD-2 (100 μg/kg). Conclusions: NSHD-1 and NSHD-2 significantly attenuate MI/R injury in a murine model. Experiments are currently underway to further define the in vivo pharmacokinetics of H2S release from these agents, mechanisms of action, and safety profile.

scholarly journals Thymoquinone dose-dependently attenuates myocardial injury induced by isoproterenol in rats via integrated modulation of oxidative stress, inflammation, apoptosis, autophagy and fibrosis

2021 ◽  
Author(s):  
Mahmoud Mohamed Farag ◽  
Asmaa Ahmed Khalifa ◽  
Wessam Fahmy El-Hadidy ◽  
Radwa Mohamed Rashad
Keyword(s):  
Oxidative Stress ◽  
Myocardial Injury ◽  
Cell Damage ◽  
Myocardial Infarct ◽  
Research Work ◽  
Radical Scavenging ◽  
Cardiac Biomarkers ◽  
Male Rats ◽  
Myocardial Infarct Size ◽  
Myocardial Oxidative Stress

Abstract As rats develop myocardial infarction (MI) like lesions when injected with large doses of isoproterenol (ISO), this investigation was designed to evaluate the effects of low and high doses of thymoquinone (TQ) on ISO-induced myocardial injury in rats. Adult male rats were divided into control, TQ20 (20 mg/kg/day), TQ50 (50 mg/kg/day), and ISO, TQ20 + ISO and TQ50 + ISO groups. In these rats, biochemical, immunobiochemical and histopathological studies were carried out to evaluate myocardial oxidative stress, inflammation, apoptosis, fibrosis and autophagy and serum cardiac biomarkers. The results showed that TQ pretreatment in ISO-administered rats produced a dose-dependent significant reduction of the myocardial infarct size, markedly reduced the ISO-induced elevation in serum cardiac markers and demonstrated several other important findings related to the cardioprotective efficacy of TQ. First, this study is the first reported research work showing that TQ treatment could increase the myocardial reduced glutathione baseline level, adding an indirect antioxidant effect to its known direct free radical scavenging effect. Second, pretreatment with TQ significantly reduced the markers of myocardial oxidative stress, inflammation, fibrosis and apoptosis. Third, TQ acted as an autophagy enhancer ameliorating myocardial cell damage and dysfunction. Thus, the changes associated with ISO-induced myocardial injury were ameliorated with TQ pretreatment. Additionally, the extent of observed improvement was significantly greater with the high TQ dose than with the low dose use. These findings raise the possibility that TQ may serve as a promising prophylactic cardioprotective therapy for patients who are at risk of developing myocardial injury as in cases of MI.

Abstract 104: Sex-specific Impact Of S-nitrosoglutathione Reductase (gsnor) On Ventricular Remodeling And Function Following Myocardial Infarction In Mice.

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Shathiyah Kulandavelu ◽  
Ellena Paulino ◽  
Lauro Takeuchi ◽  
Rosemeire Kanashiro-Takeuchi ◽  
Wayne Balkan ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ejection Fraction ◽  
Myocardial Injury ◽  
Ventricular Remodeling ◽  
Myocardial Infarct ◽  
Left Ventricular ◽  
Left Ventricular Volumes ◽  
Myocardial Infarct Size ◽  
Cardiac Protection ◽  
Ventricular Volumes

Introduction: Female hearts are less susceptible to myocardial injury following myocardial infarction (MI) and estrogen working through the nitric oxide (NO) pathway is thought to play a role. S-nitrosylation of cysteine thiols is a major signaling pathway through which NO exerts its action and mice with targeted deletion of S-nitrosoglutathione reductase (GSNOR), a denitrosylase that regulates S-nitrosylation, show increased levels of nitrosylated proteins. Male GSNOR -/- mice show a more favorable outcome after MI as compared to wild-type (WT), including reduced myocardial infarct size, improved ejection fraction and preserved left ventricular volumes. Whether female GSNOR -/- mice show gender-related cardiac protection following MI was not known and thus investigated. Methods & Results: MI was induced in male and female GSNOR -/- mice and their respective controls, C57Bl/6J, at 3-5 months via left anterior descending coronary artery occlusion. Serial echocardiography was performed prior to MI and after 1- and 4-weeks post-MI to assess ejection fraction (EF) and left ventricular volume both at diastole (end-diastolic volume, EDV) and systole (end-systolic volume, ESV). Compared to WT, GSNOR -/- males showed less dilation in both EDV (98.6 ± 9.3 mm vs. 140.6 ± 7.4 mm in WT, P<0.001) and ESV (73.1 ± 9.2 vs. 112.7 ± 7.3 mm in WT, P<0.05) at 4 weeks post-MI. Whereas, GSNOR -/- females showed greater dilation in both EDV (162.2 ± 13 vs. 83.8 ± 12 mm in WT, P<0.001) and ESV (141.8 ± 13 vs. 65.6 ± 12 mm in WT, P<0.001) as compared to WT females. EF decreased (P<0.001) in all groups post-MI, but at 4 weeks post-MI, it was significantly worse in GSNOR -/- females compared to GSNOR -/- males (14 ± 4% vs. 28 ± 3%, P<0.05). Conclusion: GSNOR -/- females exhibit significantly lower EF and greater dilation of left ventricular volumes both at diastole and systole following MI than any of the other groups suggesting that S-nitrosylation plays an important role in gender-related cardiac protection following myocardial injury. These findings suggest the importance of taking gender into account when exploring novel therapeutic treatments for myocardial injury.

scholarly journals Repeated Non-Invasive Limb Ischemic Preconditioning Confers Cardioprotection Through PKC-Ԑ/STAT3 Signaling in Diabetic Rats

2018 ◽  
Vol 45 (5) ◽  
pp. 2107-2121 ◽  
Author(s):  
Chunyan Wang ◽  
Haobo Li ◽  
Sheng Wang ◽  
Xiaowen Mao ◽  
Dan Yan ◽  
...  
Keyword(s):  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Troponin I ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Diabetic Rats ◽  
Myocardial Infarct Size ◽  
H9c2 Cells ◽  
Knock Down ◽  
Non Invasive

Background/Aims: Protein kinase C(PKC)-ε activation is a mechanism of preconditioning cardioprotection but its role in repeated non-invasive limb ischemic preconditioning (rNLIP) mediated cardioprotection against myocardial ischemia/reperfusion (I/R) injury in diabetes is unknown. Methods: Eight-week streptozotocin-induced diabetic and non-diabetic Sprague-Dawley rats were subjected to I/R without or with rNLIP. In vitro, H9C2 cells were cultured with high glucose (HG) and subjected to hypoxia/re-oxygenation (H/R) without or with PKC-ε or STAT3 gene knock-down in the absence or presence of remote time hypoxia preconditioning (HPC). Results: Diabetic rats displayed larger post-ischemic myocardial infarct size and higher troponin-I release with concomitant cardiac PKC-ԑ overexpression and activation manifested as increased membrane translocation, while phosphorylated STAT3 (p-STAT3) and Akt (p-Akt) were lower compared to non-diabetic rats (all P<0.05). rNLIP reduced infarct size in both non-diabetic and diabetic rats. rNLIP reduced post-ischemic cardiac PKC-ԑ activation in diabetic while increased PKC-ԑ activation in non-diabetic rats, resulting in increased cardiac p-STAT3 and p-Akt. In H9C2 cells, HG increased PKC-ԑ expression and exacerbated post-H/R injury, accompanied with reduced p-STAT3 and p-Akt, which were all reverted by HPC. These HPC protective effects were abolished by either PKC-ԑ or STAT3 gene knock-down, except that PKC-ԑ gene knock-down reverted HG and H/R-induced reduction of p-STAT3. Conclusion: rNLIP attenuates diabetic heart I/R injury by mitigating HG-induced PKC-ԑ overexpression and, subsequently, activating STAT3.

scholarly journals Cardiac, Energy and Hormonal Blood Markers, and Lactatemia in Cows with Displaced Abomasum

2020 ◽  
Vol 48 ◽  
Author(s):  
Ana Clara Sarzedas Ribeiro ◽  
Gliére Silmara Leite Soares ◽  
Luiz Teles Coutinho ◽  
Jobson Filipe De Paula Cajueiro ◽  
Rodolfo José Cavalcanti Souto ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Insulin Sensitivity ◽  
Myocardial Injury ◽  
Troponin I ◽  
Cardiac Biomarkers ◽  
Lower Sensitivity ◽  
Blood Concentrations ◽  
Peripheral Tissues ◽  
Creatine Kinase Mb ◽  
Cardiac Energy

Background: Displaced abomasum (DA) is a common and economically important disorder that affects dairy cattle. Nutritional factors and adaptive responses that occur in the peripartum play a central role in the pathogenesis. The measurement of blood metabolites represents a useful tool for monitoring and prognostic determination in affected animals. Therefore, the objective was to evaluate cardiac, energy and hormonal blood markers, lactatemia, and insulin sensitivity in cows diagnosed with right displaced abomasum (RDA) and left displaced abomasum (LDA), comparing them with each other.Materials, Methods & Results: Nineteen cases of abomasum displacement in cows were studied, including 9 cases of RDA and 10 cases of LDA. The diagnosis was established by means of physical examination and measurement of the concentration of chlorides in the ruminal fluid (> 30mEq/L). After diagnosis, clinical-surgical therapeutic management was instituted. At the time of diagnosis (M1) and at the resolution of the case (M2), blood samples were collected to assess the variables: non-esterified fatty acids (NEFA), beta hydroxybutyrate (βHB), L-lactate, creatine kinase (CK), creatine kinase MB (CK-MB), cardiac troponin I (cTnI), lactate dehydrogenase (LDH), glucose, insulin, and cortisol. In addition, insulin sensitivity was estimated using the Revised Quantitative Insulin Sensitivity Check Index (RQUICKI) and RQUICKI-βHB. The means of the variables were compared, separating the effects of groups (RDA and LDA) and moments (M1 and M2), at the level of 5% probability. The concentrations of NEFA, CK-MB, L-lactate, glucose, insulin, and cortisol were higher at M1 and the RQUICKI and RQUICKI-βHB indices were lower at this moment. L-lactate, CK, and CK-MB were higher in the RDA group, while cTnI, βHB, and LDH did not present a group or moment effect. Cardiac markers correlated with the energy profile metabolites, L-lactate, and cortisol.Discussion: The high concentrations of NEFA at M1 reflected the condition of negative energy balance. βHB concentrations were stable, that may be related to the number of days postpartum in which the animals were diagnosed. The hyperglycemic condition and the increase in serum cortisol concentrations found at M1 can be induced by the condition of metabolic stress resulting from the disease. Hyperinsulinemia were recorded in the present study could be an important factor related to the pathogenesis of DA, since there seems to be a correlation between hyperinsulinemia and decreased abomasal emptying rate. The RQUICKI and RQUICKI-βHB indices was significantly lower at M1, which may indicate lower sensitivity of peripheral tissues to insulin at this time. Changes in serum activity of LDH and CK may result from tissue damage due to organ displacement, in addition to damage associated with surgery and the administration of injectable drugs, mainly intramuscularly. The elevation in plasma L-lactate at M1 and in the RDA group may be associated with abomasal hypoperfusion. The high positive correlations found between L-lactate and the variables glucose, insulin, and cortisol reinforcing the association between the concentration of L-lactate and the moment of greatest stress. The increase in cardiac biomarkers may be related to the occurrence of ischemia/reperfusion injury in the abomasum, which involves oxidative stress and the production of inflammatory mediators. The hyperglycemic condition and the higher concentrations of NEFA can also contribute to the occurrence of myocardial injury. The correlations found between cardiac biomarkers and plasma L-lactate, strengthen the idea that there is a relationship between L-lactate and myocardial injury. In this sense, the measurement of blood concentrations of cTnI, CK-MB, and L-lactate could contribute as severity markers and prognosis indicators in cattle with DA. 

scholarly journals Heat Shock Protein 70 Protects the Heart from Ischemia/Reperfusion Injury through Inhibition of p38 MAPK Signaling

2020 ◽  
Vol 2020 ◽  
pp. 1-19 ◽  
Author(s):  
Nan Song ◽  
Jiao Ma ◽  
Xiao-wen Meng ◽  
Hong Liu ◽  
Hui Wang ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Heat Shock Protein 70 ◽  
Myocardial Injury ◽  
Cell Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Mapk Signaling ◽  
Myocardial Infarct Size ◽  
P38 Mapk Inhibitor ◽  
Mapk Inhibitor

Background. Heat shock protein 70 (Hsp70) has been shown to exert cardioprotection. Intracellular calcium ([Ca2+]i) overload induced by p38 mitogen-activated protein kinase (p38 MAPK) activation contributes to cardiac ischemia/reperfusion (I/R) injury. However, whether Hsp70 interacts with p38 MAPK signaling is unclear. Therefore, this study investigated the regulation of p38 MAPK by Hsp70 in I/R-induced cardiac injury. Methods. Neonatal rat cardiomyocytes were subjected to oxygen-glucose deprivation for 6 h followed by 2 h reoxygenation (OGD/R), and rats underwent left anterior artery ligation for 30 min followed by 30 min of reperfusion. The p38 MAPK inhibitor (SB203580), Hsp70 inhibitor (Quercetin), and Hsp70 short hairpin RNA (shRNA) were used prior to OGD/R or I/R. Cell viability, lactate dehydrogenase (LDH) release, serum cardiac troponin I (cTnI), [Ca2+]i levels, cell apoptosis, myocardial infarct size, mRNA level of IL-1β and IL-6, and protein expression of Hsp70, phosphorylated p38 MAPK (p-p38 MAPK), sarcoplasmic/endoplasmic reticulum Ca2+-ATPase2 (SERCA2), phosphorylated signal transducer and activator of transcription3 (p-STAT3), and cleaved caspase3 were assessed. Results. Pretreatment with a p38 MAPK inhibitor, SB203580, significantly attenuated OGD/R-induced cell injury or I/R-induced myocardial injury, as evidenced by improved cell viability and lower LDH release, resulted in lower serum cTnI and myocardial infarct size, alleviation of [Ca2+]i overload and cell apoptosis, inhibition of IL-1β and IL-6, and modulation of protein expressions of p-p38 MAPK, SERCA2, p-STAT3, and cleaved-caspase3. Knockdown of Hsp70 by shRNA exacerbated OGD/R-induced cell injury, which was effectively abolished by SB203580. Moreover, inhibition of Hsp70 by quercetin enhanced I/R-induced myocardial injury, while SB203580 pretreatment reversed the harmful effects caused by quercetin. Conclusions. Inhibition of Hsp70 aggravates [Ca2+]i overload, inflammation, and apoptosis through regulating p38 MAPK signaling during cardiac I/R injury, which may help provide novel insight into cardioprotective strategies.

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