Mechanisms of Ranolazine Pretreatment in Preventing Ventricular Tachyarrhythmias in Diabetic db/db Mice with Acute Regional Ischemia-Reperfusion Injury

2020 ◽  
Author(s):  
Chung-Chuan Chou ◽  
Hui-Ling Lee ◽  
Gwo-Jyh Chang ◽  
Hung-Ta Wo ◽  
Tzung-Hai Yen ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Decay Time ◽  
Molecular Mechanisms ◽  
Optical Mapping ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Coronary Artery Ligation ◽  
Ventricular Tachyarrhythmias ◽  
Artery Ligation

Abstract Background: Studies have demonstrated that db/db mice have increased susceptibility to myocardial ischemia-reperfusion (IR) injury and ventricular tachyarrhythmias (VA). We aimed to investigate the antiarrhythmic and molecular mechanisms of ranolazine in db/db mouse hearts with acute IR injury.Methods: Ranolazine was administered for 1 week before coronary artery ligation. Diabetic db/db and control db/+ mice were divided into ranolazine-given and -nongiven groups. IR model was created by 15-min left coronary artery ligation and 10-min reperfusion. In vivo electrophysiological studies and optical mapping to simultaneously record intracellular Ca2+ (Cai) and membrane voltage in Langendorff-perfused hearts were performed. Western blotting and whole-cell patch clamp study were performed to evaluate the effect of ranolazine in the non-IR and IR zones. Results: The severity of VA inducibility by burst pacing was higher in db/db mice than db/+ mice with acute IR injury. Ranolazine suppressed VA inducibility and severity in db/db and db/+ mice. Optical mapping studies showed that ranolazine significantly shortened action potential duration (APD80), Cai transient duration (CaiTD80), Cai decay time, ameliorated conduction inhomogeneity, and suppressed arrhythmogenic alternans induction. The expression of pThr17-phospholamban, calsequestrin 2 and SCN5A in the IR zone was significantly downregulated in db/db mice, which was ameliorated by ranolazine. Conclusions: Ranolazine pretreatment shortens APD80 and CaiTD80, reduces Cai decay time, and ameliorates conduction velocity inhomogeneity to suppress induction of arrhythmogenic alternans and VA; and amelioration of downregulation of pThr17-phospholamban, calsequestrin 2 and SCN5A may partly underlie the anti-arrhythmic molecular mechanisms of ranolazine in db/db mouse hearts with IR injury.

scholarly journals Mechanisms of ranolazine pretreatment in preventing ventricular tachyarrhythmias in diabetic db/db mice with acute regional ischemia–reperfusion injury

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Chung-Chuan Chou ◽  
Hui-Ling Lee ◽  
Gwo-Jyh Chang ◽  
Hung-Ta Wo ◽  
Tzung-Hai Yen ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Coronary Artery Ligation ◽  
Ventricular Tachyarrhythmias ◽  
Artery Ligation ◽  
Electrophysiological Studies ◽  
Myocardial Ischemia Reperfusion

AbstractStudies have demonstrated that diabetic (db/db) mice have increased susceptibility to myocardial ischemia–reperfusion (IR) injury and ventricular tachyarrhythmias (VA). We aimed to investigate the antiarrhythmic and molecular mechanisms of ranolazine in db/db mouse hearts with acute IR injury. Ranolazine was administered for 1 week before coronary artery ligation. Diabetic db/db and control db/+ mice were divided into ranolazine-given and -nongiven groups. IR model was created by 15-min left coronary artery ligation and 10-min reperfusion. In vivo electrophysiological studies showed that the severity of VA inducibility was higher in db/db mice than control (db/ +) mice. Ranolazine suppressed the VA inducibility and severity. Optical mapping studies in Langendorff-perfused hearts showed that ranolazine significantly shortened action potential duration, Cai transient duration, Cai decay time, ameliorated conduction inhomogeneity, and suppressed arrhythmogenic alternans induction. Western blotting studies showed that the expression of pThr17-phospholamban, calsequestrin 2 and voltage-gated sodium channel in the IR zone was significantly downregulated in db/db mice, which was ameliorated with ranolazine pretreatment and might play a role in the anti-arrhythmic actions of ranolazine in db/db mouse hearts with IR injury.

scholarly journals Febuxostat Modulates MAPK/NF-κBp65/TNF-α Signaling in Cardiac Ischemia-Reperfusion Injury

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Sana Irfan Khan ◽  
Rajiv Kumar Malhotra ◽  
Neha Rani ◽  
Anil Kumar Sahu ◽  
Ameesha Tomar ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Myocardial Damage ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Morphological Alterations ◽  
Treatment Groups ◽  
Antiapoptotic Proteins ◽  
Male Wistar Rats

Xanthine oxidase and xanthine dehydrogenase have been implicated in producing myocardial damage following reperfusion of an occluded coronary artery. We investigated and compared the effect of febuxostat and allopurinol in an experimental model of ischemia-reperfusion (IR) injury with a focus on the signaling pathways involved. Male Wistar rats were orally administered vehicle (CMC) once daily (sham and IR + control), febuxostat (10 mg/kg/day; FEB10 + IR), or allopurinol (100 mg/kg/day; ALL100 + IR) for 14 days. On the 15th day, the IR-control and treatment groups were subjected to one-stage left anterior descending (LAD) coronary artery ligation for 45 minutes followed by a 60-minute reperfusion. Febuxostat and allopurinol pretreatment significantly improved cardiac function and maintained morphological alterations. They also attenuated oxidative stress and apoptosis by suppressing the expression of proapoptotic proteins (Bax and caspase-3), reducing TUNEL-positive cells, and increasing the level of antiapoptotic proteins (Bcl-2). The MAPK-based molecular mechanism revealed suppression of active JNK and p38 proteins concomitant with the rise in ERK1/ERK2, a prosurvival kinase. Additionally, a reduction in the level of inflammatory markers (TNF-α, IL-6, and NF-κB) was also observed. The changes observed with febuxostat were remarkable in comparison with those observed with allopurinol. Febuxostat protects relatively better against IR injury than allopurinol by suppressing inflammation and apoptosis mediating the MAPK/NF-κBp65/TNF-α pathway.

scholarly journals Autophagic Flux Impairment Exacerbates Myocardial Ischemia-Reperfusion Injury in Experimental Diabetes Through Atg5/LAMP2 Cleavage by Calpains

2020 ◽  
Author(s):  
Lichun Guan ◽  
Ziqin Yu ◽  
Zhimei Che ◽  
Hang Zhang ◽  
Yong Yu ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Diabetic Heart ◽  
Autophagic Flux ◽  
Coronary Artery Ligation ◽  
Negative Effects ◽  
Artery Ligation ◽  
R Process ◽  
Myocardial Ischemia Reperfusion

Abstract Background: is a chronic metabolic disease characterized by hyperglycemia, which has negative effects on cardiac revascularization in patients with coronary artery disease (CAD). Methods: This study focused on the role of autophagic flux in regulating susceptibility of STZ-induced diabetic heart to ischemia-reperfusion (I/R) injury. We established STZ-induced diabetes mice and perform I/R process by coronary artery ligation, and neonatal mice cardiomyocytes culture subjected to high glucose and hypoxia/reoxygenation(H/R). Results: Diabetic heart was more sensitive to I/R injury. Autophagic flux, represented by TEM, relative LC3Ⅱ changes under CQ intervention and P62 expression, was impaired in diabetic hearts and deteriorated during subsequent I/R. Calpains were activated in diabetic I/R heart, and the inhibition of calpains partially rescued autophagic flux, cardiac function, and cell death. The expression of autophagic flux related proteins Atg5 and LAMP2 decreased significantly in diabetic I/R heart. Further studies suggested that calpain could cleave Atg5 and LAMP2, and generate cleaved fragments, which might be reversed by calpain inhibition. Inhibition of calpain，or in company with overexpression of Atg5 and LAMP2 , could reduce myocardial injury in diabetic heart subject to I/R. But overexpression of Atg5 alone could worsen the I/R injury. Conclusion: In conclusion, calpain-mediated cleavage of Atg5 and LAMP2 accounts for the impaired autophagic flux which increases the susceptibility to myocardial I/R injury in experimental diabetic mice.

scholarly journals Huang Qi Tong Bi Decoction Attenuates Myocardial Ischemia-Reperfusion Injury via HMGB1/TLR/NF-κB Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Kun Liu ◽  
Manman Li ◽  
Xiumei Ren ◽  
Qing-sheng You ◽  
Fei Wang ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Reperfusion Injury ◽  
Myocardial Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
St Segment ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

The aim of this study was to study the protective effect of Huang Qi Tong Bi Decoction (HQTBT) on the heart of rats. Ischemia-reperfusion injury was established by coronary artery ligation. Proinflammatory cytokines were decreased by XFZY in coronary artery ligated rats. ST segment was also restored with the treatment of HQTBT. Triphenyltetrazole chloride (TTC) staining and pathological analysis showed that HQTBT reduced myocardial injury. Besides, the expressions of HMGB1/TLR/NF-κB pathway in rats were significantly decreased by HQTBT. This study shows that HQTBT inhibited inflammatory reaction on myocardial injury in rats.

Abstract 16163: Hydrogen Sulfide Reduces Inflammasome Formation in Mice With Ischemic HFrEF

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Adolfo G Mauro ◽  
Juan Valle Raleigh ◽  
Khoa Nguyen ◽  
David E Durrant ◽  
Erica Kim ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
Nlrp3 Inflammasome ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Saline Control ◽  
Lv Function ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Reduced Ejection Fraction ◽  
Fractional Shortening

Background: Hydrogen sulfide (H2S) has been shown to attenuate myocardial ischemia/reperfusion injury via suppression of NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome. Whether the H2S donor, Na2S, protects against ischemic heart failure with reduced ejection fraction (HFrEF) when treatment is initiated after development of LV dysfunction is unknown. Methods and Results: Adult male mice underwent myocardial infarction (MI) by permanent coronary artery ligation after baseline echocardiography. Repeat echocardiography was performed at day 3 post MI and surviving mice with fractional shortening (FS) less than 25% were treated with either Na2S (100 μg/kg, ip) or saline (volume matched, ip) for 25 days. LV fractional shortening remained unchanged at 7 and 28 days post-MI in the saline group, but improved significantly with Na2S at both time points (Fig. A). Moreover, LV infarct scar size, assessed by trichrome staining, was smaller in Na2S group (14.8 ± 2.1%) as compared to control (28.8 ± 4.8%, P<0.05) at 7 days post MI. Immunofluorescence staining for apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), a component of the inflammasome, showed significant increase at 3 days post MI with sustained elevation at 7 days in the saline-treated group, whereas treatment with Na2S starting on day 3 post-MI significantly attenuated ASC 4 days later (Fig. B). Survival rate was 2-fold higher in Na2S group compared to saline control at 28 days post MI (P<0.05, Fig. C). Conclusion: Treatment with Na2S in mice with ischemic HFrEF improves LV function and survival up to 28 days post MI, possibly through suppression of ASC and prevention of further NLRP3 inflammasome formation. We propose that H2S donors can be promising therapeutic tools for ischemic HF.

scholarly journals Inhibition of N-type calcium channels in cardiac sympathetic neurons attenuates ventricular arrhythmogenesis in heart failure

2020 ◽  
Author(s):  
Dongze Zhang ◽  
Huiyin Tu ◽  
Chaojun Wang ◽  
Liang Cao ◽  
Wenfeng Hu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Coronary Artery ◽  
Ventricular Arrhythmias ◽  
Sympathetic Neurons ◽  
Coronary Artery Ligation ◽  
Channel Blockers ◽  
Artery Ligation ◽  
Cell Excitability ◽  
Ventricular Arrhythmogenesis

Abstract Aims Cardiac sympathetic overactivation is an important trigger of ventricular arrhythmias in patients with chronic heart failure (CHF). Our previous study demonstrated that N-type calcium (Cav2.2) currents in cardiac sympathetic post-ganglionic (CSP) neurons were increased in CHF. This study investigated the contribution of Cav2.2 channels in cardiac sympathetic overactivation and ventricular arrhythmogenesis in CHF. Methods and results Rat CHF was induced by surgical ligation of the left coronary artery. Lentiviral Cav2.2-α shRNA or scrambled shRNA was transfected in vivo into stellate ganglia (SG) in CHF rats. Final experiments were performed at 14 weeks after coronary artery ligation. Real-time polymerase chain reaction and western blot data showed that in vivo transfection of Cav2.2-α shRNA reduced the expression of Cav2.2-α mRNA and protein in the SG in CHF rats. Cav2.2-α shRNA also reduced Cav2.2 currents and cell excitability of CSP neurons and attenuated cardiac sympathetic nerve activities (CSNA) in CHF rats. The power spectral analysis of heart rate variability (HRV) further revealed that transfection of Cav2.2-α shRNA in the SG normalized CHF-caused cardiac sympathetic overactivation in conscious rats. Twenty-four-hour continuous telemetry electrocardiogram recording revealed that this Cav2.2-α shRNA not only decreased incidence and duration of ventricular tachycardia/ventricular fibrillation but also improved CHF-induced heterogeneity of ventricular electrical activity in conscious CHF rats. Cav2.2-α shRNA also decreased susceptibility to ventricular arrhythmias in anaesthetized CHF rats. However, Cav2.2-α shRNA failed to improve CHF-induced cardiac contractile dysfunction. Scrambled shRNA did not affect Cav2.2 currents and cell excitability of CSP neurons, CSNA, HRV, and ventricular arrhythmogenesis in CHF rats. Conclusions Overactivation of Cav2.2 channels in CSP neurons contributes to cardiac sympathetic hyperactivation and ventricular arrhythmogenesis in CHF. This suggests that discovering purely selective and potent small-molecule Cav2.2 channel blockers could be a potential therapeutic strategy to decrease fatal ventricular arrhythmias in CHF.

scholarly journals Mangiferin Attenuates Myocardial Ischemia-Reperfusion Injury via MAPK/Nrf-2/HO-1/NF-κB In Vitro and In Vivo

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Kun Liu ◽  
Fei Wang ◽  
Shuo Wang ◽  
Wei-Nan Li ◽  
Qing Ye
Keyword(s):  
Oxidative Stress ◽  
Coronary Artery ◽  
Myocardial Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
H9c2 Cells ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

The aim of this study was to investigate the cardioprotective effect of mangiferin (MAF) in vitro and in vivo. Oxidative stress and inflammatory injury were detected in coronary artery ligation in rats and also in hypoxia-reoxygenation- (H/R-) induced H9c2 cells. MAF inhibited myocardial oxidative stress and proinflammatory cytokines in rats with coronary artery occlusion. The ST segment of MAF treatment groups also resumed. Triphenyltetrazolium chloride (TTC) staining and pathological analysis showed that MAF could significantly reduce myocardial injury. In vitro data showed that MAF could improve hypoxia/reoxygenation- (H/R-) induced H9c2 cell activity. In addition, MAF could significantly reduce oxidative stress and inflammatory pathway protein expression in H/R-induced H9c2 cells. This study has clarified the protective effects of MAF on myocardial injury and also confirmed that oxidative stress and inflammation were involved in the myocardial ischemia-reperfusion injury (I/R) model.

An antibody to leukocyte integrins attenuates coronary vascular injury due to ischemia and reperfusion in dogs

1997 ◽  
Vol 272 (2) ◽  
pp. H618-H624 ◽  
Author(s):  
L. D. Horwitz ◽  
D. Kaufman ◽  
Y. Kong
Keyword(s):  
Coronary Artery ◽  
Leukocyte Adhesion ◽  
Microvascular Permeability ◽  
Coronary Artery Ligation ◽  
Ischemia And Reperfusion ◽  
Artery Ligation ◽  
Isotope Technique ◽  
Coronary Ischemia

Ischemia and reperfusion cause coronary vascular and myocardial injury, which may be due to leukocyte-mediated processes. Antileukocyte measures have reduced injury after brief reperfusion periods of 1-3 h, but there has been little information on whether benefits are apparent after longer periods of reperfusion. We examined the effect of pretreatment with a monoclonal antibody (R15.7) to the CD18 family of leukocyte adhesion molecules (beta2-integrins) in dogs exposed to regional coronary ischemia for 1 h of left anterior descending coronary artery ligation and then reperfused for 48 h. Coronary microvascular permeability was assessed in vivo by measurement of protein leak index (PLI), using a double-isotope technique with autologous radiolabeled transferrin and erythrocytes. Vasorelaxation was measured in vitro with preconstricted epicardial coronary artery rings subjected to increasing concentrations of the endothelium-dependent vasodilators bradykinin (BK) and ADP and the endothelium-independent vasodilator nitroprusside. At 48 h of reperfusion in untreated dogs there were substantial increases in PLI in the previously ischemic regions, indicative of increased extravascular transferrin. These abnormalities were decreased, but not abolished, in the dogs treated with R15.7. Relaxation of rings from the ischemic/reperfused artery to BK and ADP were blunted in the untreated dogs. R15.7 resulted in improvement in some, but not all, indexes of relaxation in response to BK and ADP. Relaxation to nitroprusside was normal in ischemic/reperfused coronary rings from both treated and untreated dogs. Therefore, after 1 h of regional coronary ischemia and 48 h of reperfusion, coronary endothelial injury, which was manifested by increased coronary microvascular permeability and abnormalities in coronary endothelium-dependent relaxation, was reduced by pretreatment with the anti-CD18 integrin antibody R15.7.

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