Protective effect of trimetazidine on myocardial mitochondrial function in an ex-vivo model of global myocardial ischemia

Monteiro, Pedro; Duarte, Ana I.; Gonçalves, Lino; Moreno, António J.; Providência, Luí­s A.

doi:10.1016/j.ejphar.2004.09.003

Cited by 43 publications

(23 citation statements)

References 16 publications

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“…Other reports showed that ANG II inhibition improved cardiac mitochondria energy production (289,290,307), and in diabetic rats captopril treatment upregulated the expression of genes related to energy production (74). Among the potential factor(s) that may mediate the effects of ANG II inhibitors on mitochondrial function, mitochondrial NO was suggested to contribute to the renal mitochondrial actions of enalapril (317), and ARBs were found to modulate UCP mRNA levels in mouse brown adipose tissue (12) and rat liver (78), or UCP protein content in rat kidney (103,317).…”

Section: Ras-bl and Agingmentioning

confidence: 99%

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

Cavanagh

Inserra

Ferder

2015

American Journal of Physiology-Heart and Circulatory Physiology

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de Cavanagh EM, Inserra F, Ferder L. Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition. Am J Physiol Heart Circ Physiol 309: H15-H44, 2015. First published May 1, 2015; doi:10.1152/ajpheart.00459.2014, renin angiotensin system blockade (RAS-bl), and rapamycin-mediated mechanistic target of rapamycin (mTOR) inhibition increase survival and retard aging across species. Previously, we have summarized CR and RAS-bl's converging effects, and the mitochondrial function changes associated with their physiological benefits. mTOR inhibition and enhanced sirtuin and KLOTHO signaling contribute to the benefits of CR in aging. mTORC1/mTORC2 complexes contribute to cell growth and metabolic regulation. Prolonged mTORC1 activation may lead to age-related disease progression; thus, rapamycin-mediated mTOR inhibition and CR may extend lifespan and retard aging through mTORC1 interference. Sirtuins by deacetylating histone and transcription-related proteins modulate signaling and survival pathways and mitochondrial functioning. CR regulates several mammalian sirtuins favoring their role in aging regulation. KLOTHO/fibroblast growth factor 23 (FGF23) contribute to control Ca 2ϩ , phosphate, and vitamin D metabolism, and their dysregulation may participate in age-related disease. Here we review how mTOR inhibition extends lifespan, how KLOTHO functions as an aging suppressor, how sirtuins mediate longevity, how vitamin D loss may contribute to age-related disease, and how they relate to mitochondrial function. Also, we discuss how RAS-bl downregulates mTOR and upregulates KLOTHO, sirtuin, and vitamin D receptor expression, suggesting that at least some of RAS-bl benefits in aging are mediated through the modulation of mTOR, KLOTHO, and sirtuin expression and vitamin D signaling, paralleling CR actions in age retardation. Concluding, the available evidence endorses the idea that RAS-bl is among the interventions that may turn out to provide relief to the spreading issue of age-associated chronic disease. mechanistic target of rapamycin; vitamin D; caloric restriction; renin-angiotensin system EFFORTS AIMED AT DECIPHERING the mechanisms that underlie the aging process have unveiled three interventions that can increase survival and retard age-related diseases from lower organisms to mammals, i.e., caloric restriction (CR) (84,85,140,160,334), mechanistic target of rapamycin (mTOR; originally mammalian TOR) inhibition by rapamycin (173,196,281), and renin-angiotensin system blockade (RAS-bl) (20, 21, 26,63,253,284,354), although the latter has been less studied. In light of these findings, some intriguing questions come to mind: Do these interventions attenuate aging by interfering with common mechanisms? Do the mechanisms that are interfered with by CR, rapamycin, and RAS-bl mutually affect each other? Are there any pathways involved exclusively with a certain intervention?Previously (101), we have discussed the converging effects d...

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Section: Ras-bl and Agingmentioning

confidence: 99%

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

Cavanagh

Inserra

Ferder

2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…The precise mechanism by which trimetazidine partially inhibits FAO remains controversial; some investigators advocate a selective inhibition of long-chain 3-ketoacyl CoA thiolase, 139 whereas other investigators reject this. 140 Trimetazidine has additional effects, 141 such as mitochondrial protection, 142 lessened proton production, 143 and endothelial protection. 144 Thus, although trimetazidine has in part delivered on the promise of metabolic modulation in human HF (Table 3), 138,[145][146][147][148][149][150][151][152][153][154][155] it is unlikely to be marketed for HF because of patent issues.…”

Section: Decrease Of Fatty Acid Metabolism By Fatty Acid Oxidation Inmentioning

confidence: 99%

Metabolic Mechanisms in Heart Failure

Ashrafian

Frenneaux

Opie³

2007

Circulation

462

301

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Abstract-Although neurohumoral antagonism has successfully reduced heart failure morbidity and mortality, the residual disability and death rate remains unacceptably high. Though abnormalities of myocardial metabolism are associated with heart failure, recent data suggest that heart failure may itself promote metabolic changes such as insulin resistance, in part through neurohumoral activation. A detrimental self-perpetuating cycle (heart failure 3 altered metabolism 3 heart failure) that promotes the progression of heart failure may thus be postulated. Accordingly, we review the cellular mechanisms and pathophysiology of altered metabolism and insulin resistance in heart failure. It is hypothesized that the ensuing detrimental myocardial energetic perturbations result from neurohumoral activation, increased adverse free fatty acid metabolism, decreased protective glucose metabolism, and in some cases insulin resistance. The result is depletion of myocardial ATP, phosphocreatine, and creatine kinase with decreased efficiency of mechanical work. On the basis of the mechanisms outlined, appropriate therapies to mitigate aberrant metabolism include intense neurohumoral antagonism, limitation of diuretics, correction of hypokalemia, exercise, and diet. We also discuss more novel mechanistic-based therapies to ameliorate metabolism and insulin resistance in heart failure. For example, metabolic modulators may optimize myocardial substrate utilization to improve cardiac function and exercise performance beyond standard care. The ultimate success of metabolic-based therapy will be manifest by its capacity further to lessen the residual mortality in heart failure. Key Words: fatty acids Ⅲ glucose Ⅲ heart failure Ⅲ insulin resistance D espite significant therapeutic advances, heart failure (HF) remains a leading cause of morbidity and mortality in developed 1 and increasingly in developing countries, 2 with a 5-year mortality rate of Ϸ50%, which rivals or exceeds that of many cancers. 3 This unacceptably high residual mortality and morbidity has mandated a reevaluation of cardiac biology with the aim to identify novel therapeutic strategies for HF. Because the daily turnover of ATP (Ϸ6 to 35 kg) is very many times that of the myocardial ATP pool, and even the healthy heart only extracts Ϸ25% of energy derivable from substrates, 4 it is not surprising that even subtle variations in the efficiency of energy generation or utilization may have a profound cumulative impact on cellular energy levels. 5 Thus cardiac energetics in particular and metabolism in general represent promising targets for HF therapy. 6 Correspondingly, numerous studies have identified decreased cardiac energy levels and flux as a consistent feature of HF. 6,7 These observations have been reinforced by genomic studies 8 and have focused considerable attention on metabolic modulation as a therapy for HF. 6 Specifically, altered myocardial carbohydrate metabolism and the related state of myocardial insulin resistance (IR), in which given concentrations of...

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“…Under ischemic conditions, TMZ is known to improve mitochondrial metabolism by decreasing oxygen consumption (Monteiro et al, 2004). To check whether TMZ treatment affected oxygen consumption by MSCs under the given experimental conditions, we determined the OCR of the cells using EPR oximetry.…”

Section: Effect Of Hypoxia and H 2 O 2 On The Viability Of Mscsmentioning

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

J Pharmacol Exp Ther

122

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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.

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Protective effect of trimetazidine on myocardial mitochondrial function in an ex-vivo model of global myocardial ischemia

Cited by 43 publications

References 16 publications

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

Metabolic Mechanisms in Heart Failure

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

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