Trimetazidine, Administered at the Onset of Reperfusion, Ameliorates Myocardial Dysfunction and Injury by Activation of p38 Mitogen-Activated Protein Kinase and Akt Signaling

Abstract

Trimetazidine [1-(2,3,4-trimethoxybenzyl)piperazine; TMZ] is an anti-ischemic cardiac drug; however, its efficacy and mechanism of cardioprotection upon reperfusion are largely unknown. The objective of this study was to determine whether TMZ, given before reperfusion, could attenuate myocardial reperfusion injury. Ischemia/reperfusion (I/R) was induced in rat hearts by ligating the left anterior descending (LAD) coronary artery for 30 min followed by 48 h of reperfusion. TMZ (5 mg/kg b.wt.) was administered 5 min before reperfusion. The study used three experimental groups: control (ϪI/R; ϪTMZ), I/R (ϩI/R; ϪTMZ), and TMZ (ϩI/R; ϩTMZ). Echocardiography and EPR oximetry were used to assess cardiac function and oxygenation, respectively. The ejection fraction, which was significantly depressed in the I/R group (62 Ϯ 5 versus 84 Ϯ 3% in control), was restored to 72 Ϯ 3% in the TMZ group. Myocardial pO 2 in the TMZ group returned to baseline levels (ϳ20 mm Hg) within 1 h of reperfusion, whereas the I/R group showed a significant hyperoxygenation even after 48 h of reperfusion. The infarct size was significantly reduced in the TMZ group (26 Ϯ 3 versus 47 Ϯ 5% in I/R). TMZ treatment significantly attenuated superoxide levels in the tissue. Tissue homogenates showed a significant increase in p38 and p-Akt and decrease in caspase-3 levels in the TMZ group. In summary, the results demonstrated that TMZ is cardioprotective when administered before reperfusion and that this protection appears to be mediated by activation of p38 mitogen-activated protein kinase and Akt signaling. The study emphasizes the importance of administering TMZ before reflow to prevent reperfusion-mediated cardiac injury and dysfunction.Ischemic heart disease is the leading cause of mortality among both men and women in the United States, and in the world. Clinical interventions such as coronary angioplasty, coronary artery bypass graft surgery, or percutaneous transluminal coronary angioplasty are routinely used to reintroduction of blood flow to an ischemic region of the myocardium. Such interventions are unavoidably accompanied by an enzymatic cascade of reactions that result in damage to the myocardium, termed ischemia/reperfusion (I/R) injury.Although the etiology of I/R injury is intricate, oxidative stress occurs due to an imbalance between free-radical production and the heart's ability to prevent the damage caused by free radicals. Numerous studies have shown that the generation of reactive oxygen species (ROS) in the oxygendeprived tissue plays a crucial role in the cellular oxidative damage that happens during I/R (Zweier et al., 1989;Ambrosio et al., 1993;Griendling and FitzGerald, 2003). The generation of free radicals that occurs during I/R has been reported by several groups (Bolli et al., 1988;Zweier et al., 1989) and has revealed that ROS production peaks within the first few minutes of reperfusion. Free-radical scavengers (e.g., antioxidants) have been shown to protect the heart from oxidative damage resulting from the form...

Effects of trimetazidine on the Akt/eNOS signaling pathway and oxidative stress in anin vivorat model of renal ischemia-reperfusion

“…Previous reports demonstrated the activation of Akt/eNOS signaling pathway to mitigate I/R induced oxidative stress. Khan and colleagues 32 reported that TMZ is cardioprotective when administered before reperfusion and that this protection appears to be mediated by activation of p38 mitogen-activated protein kinase and Akt signaling pathway. Recently, Wu and coworkers 31 demonstrated that TMZ ameliorated H 2 O 2 -induced impairment of biological functions in endothelial progenitor cells with involvement of antioxidation and Akt/eNOS signaling pathways.…”

Effectiveness of a single versus repeated administration of trimetazidine in the protection against warm ischemia/reperfusion injury of rat liver

“…Khan et al (9) reported that TMZ is cardioprotective when administered before reperfusion and that this protection appears to be mediated by activation of p38 mitogen-activated protein kinase and Akt signaling pathway. Moreover, Wu et al (18) demonstrated that TMZ induced the activation of Akt/eNOS signaling pathways to mitigate H 2 O 2 induced oxidative stress and cell death.…”

“…We noted that repeated administration of TMZ for 3 days was more efficient in reducing liver damage than a single dose. A growing body of evidence has proven that TMZ has antioxidant effects and its role on lipid peroxidation inhibition has been well established in different organs (8,9). Lipid peroxidation disrupts membrane fluidity and cell compartmentalization, which results in cell lysis (3).…”

“…Several routes, times, and doses of administration of this antioxidant agent have been proposed in the literature (5,8,9). Tsimoyiannis et al (10) demonstrated that a single dose of TMZ (2.5 mg/kg) given before or after the ischemic episode gave significant protection to hepatocytes, but pretreatment twice for 5 days was more effective.…”

Rationale for Application, and Benefits of Trimetazidine in Heart Failure by Its Influence of Myocardium Metabolism

“…Наблюдаемое увеличение отношения КФ/АТФ, выз-ванное триметазидином, указывает на то, что данный препарат может быть способным обеспечивать под-держание даже более высоких уровней высокоэнерге-тического фосфата. В дополнение к большей выра-ботке высокоэнергетического фосфата триметазидин улучшает эндотелиальную функцию, уменьшает перегрузку клеток кальцием и вызванное свобод-ными радикалами повреждение, а также подавляет апоптоз клеток и фиброз сердца [43][44][45][46][47].…”