Manipulation of cardiac metabolism and oxidative stress

Ioana Holban
Centre Hospitalier Frédéric Joliot, Paris, France
Correspondence: Dr Ioana Holban, Centre Hospitalier Frédéric Joliot,
4, pl Gén. Leclerc, 91400 Orsay, France, tel: +33 1 6986 7700

Cardiomyocytes suppress contraction and oxygen consumption during hypoxia. Oxidative stress increases the generation of reactive oxygen species by altering mitochondrial reactions. During postischemic reperfusion, for example, reactive oxygen species are formed at an accelerated rate and the defense mechanisms against oxygen free radicals are also altered.
Exposure of myocardial cellular components to exogenous reactive oxygen species could lead to cellular dysfunction and necrosis. There is strong evidence that reactive oxygen species are mediators of the reversible ventricular dysfunction (stunning) that often accompanies reperfusion [1]. The widespread introduction of fibrinolysis and PTCA in the treatment of myocardial infarction has changed the outlook of modern cardiology, but it also raises new problems. One is the occurrence of extensive tissue injury caused by reperfusion, with the generation of oxygen free radicals. Trimetazidine (Vastarel 20 mg) is a well-established anti-ischemic drug belonging to a new class of metabolic agents known as 3-ketoacyl-CoA-thiolase inhibitors. It has been used for the treatment of conditions related to the generation of reactive oxygen species. The ability of trimetazidine to protect low-density lipoproteins from oxidation, and cultured cells from H2O2-induced DNA damage, has been investigated and the results indicate that this agent can modulate the action of oxidants in different systems [2]. In one study performed in patients with ischemic heart disease who underwent coronary angiography, it was found that this intervention provokes oxidative stress and membrane-destructive processes. Trimetazidine given 10 days before the procedure was shown to produce a cytoprotective effect [3].
Evidence that trimetazidine has antioxidant effects is suggested by reduced accumulation of free radicals in experimental conditions of high oxidative stress. Clinical trial data concluded that 1 month’s therapy with trimetazidine significantly decreased the content of free radical oxidation products in patients with ischemic heart disease. These data suggest that trimetazidine’s antioxidant effect is indirectly mediated via activation of antioxidant enzymes, which diminishes the tissue damage caused by ischemia [4].
Interestingly, chronic release of reactive oxygen species has recently been limited to heart failure progression [5]. The release of reactive oxygen species appears to derive from the nonphagocytic (reduced) nicotinamide adenine dinucleotide phosphate oxidase and mitochondria. Fibrosis, collagen deposition and metalloprotease activation involved in the progression of heart failure are dependent on the release of reactive oxygen species. A study conducted by Belardinelli et al [6] aimed to assess the antioxidant effects of trimetazidine in patients with documented coronary artery disease and left ventricular systolic dysfunction. Lipid peroxidation product malonyldialdehyde (MDA) and lipid hydroperoxides (LOOH) were measured, and endothelium-dependent and -independent vasodilatation of radical artery was determined on study entry and after 4 weeks’ treatment with trimetazidine or placebo. The findings of the study suggest that trimetazidine reduces both plasma MDA and LOOH levels (Figure 1) along with endothelial dysfunction and improves functional capacity in patients with chronic heart failure. These benefits are likely to be linked to the antioxidant properties of trimetazidine.

Figure 1. Reduction in lipid peroxidation products after 8 weeks’ treatment with trimetazidine.

The therapeutic potential of free radical-directed drugs in heart disease has not been fully investigated. Due to its specific metabolic mode of action free of any hemodynamic impact and its excellent tolerance, trimetazidine appears to be an interesting therapeutic option to protect tissues from ischemia-induced oxidative stress.

REFERENCES

 
Trimetazidine protects low-density lipoproteins from oxidation and cultured cells exposed to H(2)O(2) from DNA damage.

Tselepis A, Doulias P, Lourida E, Glantzounis G, Tsimoyiannis E, Galaris D.

Laboratory of Biochemistry, Department of Chemistry, University of Ioannina, Ioannina, Greece.

Trimetazidine is a well-established anti-ischemic drug, which has been used for long time in the treatment of pathological conditions related with the generation of reactive oxygen species. However, although extensively studied, its molecular mode of action remains largely unknown. In the present study, the ability of trimetazidine to protect low-density lipoproteins (LDL) from oxidation and cultured cells from H(2)O(2)-induced DNA damage was investigated. Trimetazidine, tested at concentrations 0.02 to 2.20 mM, was shown to offer significant protection to LDL exposed to three different oxidizing systems, namely copper, Fe/ascorbate, and met-myoglobin/H(2)O(2). The oxidizability of LDL was estimated by measuring, (i) the lag period, (ii) the maximal rate of conjugated diene formation, (iii) the total amount of conjugated dienes formed, (iv) the electrophoretic migration of LDL protein in agarose gels (REM), and (v) the inactivation of the enzyme PAF-acetylhydrolase present in LDL. In addition, the presence of trimetazidine decreased considerably the DNA damage in H(2)O(2)-exposed Jurkat cells in culture. H(2)O(2) was continuously generated by the action of glucose oxidase at a rate of 11.8 +/- 1.5 microM per min (60 ng enzyme per 100 microl), and DNA damage was assessed by the single cell gel electrophoresis assay (also called comet assay). The protection offered by trimetazidine in this system (about 30% at best) was transient, indicating modification of this agent during its action. These results indicate that trimetazidine can modulate the action of oxidizing agents in different systems. Although its mode of action is not clarified, the possibility that it acts as a lipid barrier permeable transition metal chelator is considered.

PMID: 11390180 [PubMed - indexed for MEDLINE]

 
Reactive oxygen species, mitochondria, and NAD(P)H oxidases in the development and progression of heart failure.

Sorescu D, Griendling KK.

Emory University School of Medicine, Department of Medicine, Division of Cardiology, Atlanta, GA 30322, USA.

Reactive oxygen species (ROS) released acutely in large amounts have been traditionally implicated in the cell death associated with myocardial infarction or reperfusion injury. These ROS can be released from the cardiac myocyte mitochondria, xanthine oxidase, and the phagocytic nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase. Interestingly, the chronic release of ROS has been recently linked to the development of left ventricular hypertrophy and heart failure progression. The chronic release of ROS appears to derive from the nonphagocytic NAD(P)H oxidase and mitochondria. Experimental data are accumulating suggesting that the release of ROS is required for the normal, physiologic activity of cardiac cells, but abnormal activation of the nonphagocytic NAD(P)H oxidase in response to neurohormones (angiotensin II, norepinephrine, tumor necrosis factor-a) has been shown to contribute to cardiac myocyte hypertrophy. Furthermore, the fibrosis, collagen deposition, and metalloproteinase activation involved in the remodeling of the failing myocardium are dependent on ROS released during the phenotypic transformation of fibroblasts to myofibroblasts associated with progression of end-stage heart failure. Future studies are necessary to identify the sources, mechanisms of activation of NAD(P)H oxidases, and downstream signaling targets implicated in the progression of chronic heart failure. Copyright 2002 CHF, Inc.

Publication Types:

• Review
• Review, Tutorial

PMID: 12045381 [PubMed - indexed for MEDLINE]

6. Belardinelli R, Solenghi M, Volpe L. Effects of trimetazidine on endothelial dysfunction on chronic heart failure: an antioxidant effect? Circulation. 2001;104(17 suppl):II–337.