Trimetazidine protects isolated rat hearts against ischemia?reperfusion injury in an experimental timing ? dependent manner

Trimetazidine (TMZ), an anti-ischemic metabolic drug, is used to treat chest pain (angina pectoris). We hypothesized that derivatives of TMZ with antioxidant functions may improve the cardiac dysfunction caused by ischemia-reperfusion (I/R) above that observed with TMZ alone. Isolated rat hearts perfused with Krebs-Henseleit buffer according to the Langendorff method were subjected to 30 min of global ischemia followed by 45 min of reperfusion. Trimetazidine, TMZ-NH (TMZ modified with a pyrroline moiety), or TMZ-⌽NH (TMZ-NH with a phenyl substitute) were infused (50 M) for 1 min before the onset of ischemia. Untreated (control) hearts at the end of 45 min of reperfusion showed a significant decrease in the recovery of coronary flow (42%), left ventricular-developed pressure (22%), and rate-pressure product (25%) compared with preischemic baseline values. The I/R hearts also showed markedly increased lactate dehydrogenase and creatine kinase activities in the coronary effluent, significant myocardial infarction (46% of risk area), and activation of Akt, extracellular signal-regulated kinase, and p38 mitogen-activated protein kinase. Pretreatment of hearts with TMZ-NH or TMZ-⌽NH significantly enhanced the recovery of heart function and decreased infarct size. The I/R-induced activation of Akt was further enhanced by TMZ-⌽NH. The present study demonstrated that TMZ-NH and TMZ-⌽NH significantly protected hearts against I/R-mediated cardiac dysfunction and injury. The protective effect of the TMZ derivatives could be due to the combined effects of antioxidant and anti-ischemic activities as well as enhanced pro-survival Akt activity.

Section: Discussionsupporting

confidence: 83%

mentioning

confidence: 99%

Attenuation of Myocardial Ischemia-Reperfusion Injury by Trimetazidine Derivatives Functionalized with Antioxidant Properties

Kutala

Khan

Mandal

et al. 2006

“…At the cellular level, TMZ preserves ATP production, reduces the generation of oxygen free radicals (Maupoil et al, 1990;Gambert et al, 2006;Kutala et al, 2006), and reduces intracellular acidosis and calcium overload (Kantor et al, 2000). TMZ has been shown to protect hearts from ischemia-induced electrical dysfunction leading to ventricular fibrillation (Vaillant et al, 2008), ischemia-reperfusion-induced damage to mitochondrial respiration (Guarnieri and Muscari, 1993), and ischemia-reperfusion injury by decreasing myocardial lactate content early at reperfusion (Pantos et al, 2005). Tritto et al (2005) demonstrated that TMZ attenuated tissue injury in postischemic hearts by inhibiting the activation of neutrophils.…”

Section: Preconditioning Of Mscs With Trimetazidine For Cell Therapy 547mentioning

confidence: 99%

Pharmacological Preconditioning of Mesenchymal Stem Cells with Trimetazidine (1-[2,3,4-Trimethoxybenzyl]piperazine) Protects Hypoxic Cells against Oxidative Stress and Enhances Recovery of Myocardial Function in Infarcted Heart through Bcl-2 Expression

Wisel¹,

Khan²,

Kuppusamy³

et al. 2009

122

Stem cell transplantation is a possible therapeutic option to repair ischemic damage to the heart. However, it is faced with a number of challenges including the survival of the transplanted cells in the ischemic region. The present study was designed to use stem cells preconditioned with trimetazidine (1-[2,3,4-trimethoxybenzyl]piperazine; TMZ), a widely used anti-ischemic drug for treating angina in cardiac patients, to increase the rate of their survival after transplantation. Bone marrow-derived rat mesenchymal stem cells (MSCs) were subjected to a simulated host tissue environment by culturing them under hypoxia (2% O 2 ) and using hydrogen peroxide (H 2 O 2 ) to induce oxidative stress. MSCs were preconditioned with 10 M TMZ for 6 h followed by treatment with 100 M H 2 O 2 for 1 h and characterized for their cellular viability and metabolic activity. The preconditioned cells showed a significant protection against H 2 O 2 -induced loss of cellular viability, membrane damage, and oxygen metabolism accompanied by a significant increase in HIF-1␣, survivin, phosphorylated Akt (pAkt), and Bcl-2 protein levels and Bcl-2 gene expression. The therapeutic efficacy of the TMZ-preconditioned MSCs was evaluated in an in vivo rat model of myocardial infarction induced by permanent ligation of left anterior descending coronary artery. A significant increase in the recovery of myocardial function and up-regulation of pAkt and Bcl-2 levels were observed in hearts transplanted with TMZ-preconditioned cells. This study clearly demonstrated the potential benefits of pharmacological preconditioning of MSCs with TMZ for stem cell therapy for repairing myocardial ischemic damage.

“…It reduces oxidative damage to the mitochondria and protects the heart from I/R-induced damage arising from mitochondrial respiration (Guarnieri and Muscari, 1993). TMZ has also shown cytoprotective efficacy in several models of myocardial infarction (Harpery et al, 1989;Pantos et al, 2005). In addition to its beneficial effects in the treatment of I/R injury, TMZ has been reported to provide modest protection to postischemic hearts by improving left ventricular function in patients with chronic coronary artery disease or ischemic cardiomyopathy and in patients experiencing acute periods of ischemia when undergoing percutaneous transluminal coronary angioplasty (McClellan and Plosker, 1999).…”

mentioning

confidence: 99%

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

Khan¹,

Meduru²,

Mostafa³

et al. 2010

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...