Cardioprotection by curcumin post-treatment in rats with established chronic kidney disease.

PURPOSE: The pathogenic mechanisms leading to cardiovascular disorders in patients with chronic kidney disease have not been clearly established, although increased oxidative stress has been pointed out as a potential cause. Therefore, as cardiovascular events are still the first cause of death in patients with chronic kidney disease and traditional drugs or therapies rarely have effects on cardiac complications, we sought to determine the effect of curcumin in treating cardiac dysfunction in rats with established chronic renal disease. METHODS AND RESULTS: Treatment consisted in daily administration of curcumin (120 mg/kg/day) dissolved in 0.05% carboxymethylcellulose via oral gavages during 30 days, beginning from day 30 after 5/6 nephrectomy (5/6Nx). Cardiac function, markers of oxidative stress, activation of PI3K/Akt/GSK3ß and MEK1/2-ERK1/2 pathway, metalloproteinase-II (MMP-2) content, overall gelatinolytic activity, ROS production and mitochondrial integrity were evaluated after 1-month treatment. Curcumin restored systolic blood pressure, diminished interventricular and rear wall thickening, decreased left ventricle dimension at end-systole (LVSd) and restored ejection fraction in nephrectomized rats. Also, it diminished metalloproteinase-II levels and overall gelatinase activity, decreased oxidative stress and inhibited the mitochondrial permeability transition pore opening. CONCLUSION: Our findings suggest that curcumin might have therapeutic potential in treatment of heart disease in patients with established CKD by attenuating oxidative stress-related events as cardiac remodeling, mitochondrial dysfunction and cell death.

Reduction of no-reflow and reperfusion injury with the synthetic 17ß-aminoestrogen compound Prolame is associated with PI3K/Akt/eNOS signaling cascade.

A high proportion of primary percutaneous coronary interventions performed in the setting of acute myocardial infarction, concur with inadequate myocardial perfusion at the microvascular level. This phenomenon, known as "no-reflow" contributes to reperfusion injury, poor prognosis and to unfavorable clinical outcome. In this study, we evaluated the hypothesis that the synthetic 17ß-aminoestrogen Prolame, may confer cardioprotection and prevent against no-reflow. In an open-chest model of 30-min ischemia and 90-min reperfusion, male Wistar rats were randomly assigned to different groups: Control, Prolame, Prolame followed by the nitric oxide synthase inhibitor (L-NAME), and 17ß-estradiol. Areas of risk, infarct size and no-reflow were determined by planimetry with triphenyltetrazolium chloride and thioflavin-S stains. Structural damage of the vasculature was measured as capillary compression in clarified tissue after intra-atrial injection of Microfil. Hemodynamic function was obtained at the end of stabilization, ischemia and reperfusion; nitric oxide (NO·) content was determined indirectly using the Griess reaction. Activation of the eNOS signaling cascade was determined by western blot. Prolame reduced the infarcted area, decreased the zones of no-reflow and capillary compression by activating the PI3K/Akt/eNOS signaling pathway in correlation with NO· increase. Prolame also activated endothelial cells augmenting NO· production, which was inhibited by ICI182780 (a selective estrogen receptor down-regulator), supporting the notion that the cardioprotective effect of Prolame involves the preservation of endothelium through the activation of estrogen receptor downstream signaling. Our results provide evidence that Prolame has potential therapeutic application in patients with AMI, as it prevents from both vascular and cardiac tissue damage.

PHO-ERK1/2 interaction with mitochondria regulates the permeability transition pore in cardioprotective signaling.

AIMS: The molecular mechanism(s) by which extracellular signal-regulated kinase 1/2 (ERK1/2) and other kinases communicate with downstream targets have not been fully determined. Multiprotein signaling complexes undergoing spatiotemporal redistribution may enhance their interaction with effector proteins promoting cardioprotective response. Particularly, it has been proposed that some active kinases in association with caveolae may converge into mitochondria. Therefore, in this study we investigate if PHO-ERK1/2 interaction with mitochondria may provide a mechanistic link in the regulation of these organelles in cardioprotective signaling. MAIN METHODS: Using a model of dilated cardiomyopathy followed by ischemia-reperfusion injury, we determined ERK1/2 signaling at the level of mitochondria and evaluated its effect on the permeability transition pore. KEY FINDINGS: The most important finding of the present study is that, under cardioprotective conditions, a subpopulation of activated ERK1/2 was directed to the mitochondrial membranes through vesicular trafficking, concurring with increased phosphorylation of mitochondrial proteins and inhibition of the mitochondrial permeability transition pore opening. In addition, our results suggest that vesicles enriched with caveolin-3 could form structures that may drive ERK1/2, GSK3ß and Akt to mitochondria. SIGNIFICANCE: Signaling complexes including PHO-ERK, PHO-Akt, PHO-eNOS and caveolin-3 contribute to cardioprotection by directly targeting the mitochondrial proteome and regulating the opening of the permeability transition pore in this model.

Curcumin maintains cardiac and mitochondrial function in chronic kidney disease.

Curcumin, a natural pigment with antioxidant activity obtained from turmeric and largely used in traditional medicine, is currently being studied in the chemoprevention of several diseases for its pleiotropic effects and nontoxicity. In chronic renal failure, the pathogenic mechanisms leading to cardiovascular disorders have been associated with increased oxidative stress, a process inevitably linked with mitochondrial dysfunction. Thus, in this study we aimed at investigating if curcumin pretreatment exerts cardioprotective effects in a rat model of subtotal nephrectomy (5/6Nx) and its impact on mitochondrial homeostasis. Curcumin was orally administered (120mg/kg) to Wistar rats 7 days before nephrectomy and after surgery for 60 days (5/6Nx+curc). Renal dysfunction was detected a few days after nephrectomy, whereas changes in cardiac function were observed until the end of the protocol. Our results indicate that curcumin treatment protects against pathological remodeling, diminishes ischemic events, and preserves cardiac function in uremic rats. Cardioprotection was related to diminished reactive oxygen species production, decreased oxidative stress markers, increased antioxidant response, and diminution of active metalloproteinase-2. We also observed that curcumin's cardioprotective effects were related to maintaining mitochondrial function. Aconitase activity was significantly higher in the 5/6Nx + curc (408.5±68.7nmol/min/mg protein) than in the 5/6Nx group (104.4±52.3nmol/min/mg protein, P<0.05), and mitochondria from curcumin-treated rats showed enhanced oxidative phosphorylation capacities with both NADH-linked substrates and succinate plus rotenone (3.6±1 vs 1.1±0.9 and 3.1±0.7 vs 1.2±0.8, respectively, P<0.05). The mechanisms involved in cardioprotection included both direct antioxidant effects and indirect strategies that could be related to protein kinase C-activated downstream signaling.

Targeting mitochondria for cardiac protection.

The critical role of mitochondria in cardiomyocyte survival and death has become an exciting field of research in cardiac biology. Indeed, it is accepted that mitochondrial dysfunction plays a crucial role in the pathogenesis of multiple cardiac diseases. Besides the obvious relevance of mitochondria in energy production, calcium homeostasis, and reactive oxygen species (ROS) production, new processes like mitochondrial fusion/fission, phosphorylation and nitrosylation modifications in mitochondrial proteins have been suggested to form part of a cast of key players in cardiac disease. This review describes currently studied drugs and compounds that target mitochondria in the scenario of cardiovascular diseases.

Protective effect of α-mangostin on cardiac reperfusion damage by attenuation of oxidative stress.

This study was designed to investigate if α-mangostin (α-M), a xanthone present in the pericarp of Garcinia mangostana L., was able to protect against reperfusion injury in Langendorff-reperfused hearts. It was observed that α-M maintains the cardiac mechanical work, diminishes the area of infarct, and prevents the decrease in cardiac ATP and phosphocreatine levels in the reperfused myocardium. The protective effect of this xanthone was associated with reduction of oxidative stress. α-M treatment prevented reperfusion injury-induced protein oxidation (protein carbonyl content), lipid peroxidation (malondialdehyde and 4-hydroxynonenal content), and diminution of glutathione content. In fact, after α-M treatment, the values in these parameters were comparable to those obtained in nonreperfused hearts. In summary, α-M induces a protective effect in postischemic heart associated to the prevention of oxidative stress secondary to reperfusion injury.

Protective behavior of tamoxifen against Hg2+-induced toxicity on kidney mitochondria: in vitro and in vivo experiments.

Heavy metals are known to induce functional alterations in kidney mitochondria, this damage plays a central role in the mercury-induced acute renal failure. In fact, mercury causes rapid and dramatic changes in the membrane's ionic permeability in such a way that a supra load of mitochondrial Ca(2+) occurs. As a consequence, the phenomenon of permeability transition takes place. In this work we studied in vitro and in vivo the protective effect of the selective estrogen receptor modulator tamoxifen on the deleterious action of mercury-induced nonselective permeability in kidney mitochondria. Added in vitro tamoxifen inhibited membrane nonspecific pore opening, brought about by Hg(2+), as well as the oxidative damage of the enzyme cis-aconitase. In vivo the administration of tamoxifen prevented Hg(2+)-induced poisoning on mitochondrial energy-dependent functions. Permeability transition was analyzed by measuring matrix Ca(2+) retention, mitochondrial swelling, and the build up and maintenance of a transmembrane electric gradient. The pharmacologic action of tamoxifen on mercury poisoning could be ascribed to its cyclosporin-like action.