MitoQ improves mitochondrial dysfunction in heart failure induced by pressure overload.

Heart failure remains a major public-health problem with an increase in the number of patients worsening from this disease. Despite current medical therapy, the condition still has a poor prognosis. Heart failure is complex but mitochondrial dysfunction seems to be an important target to improve cardiac function directly. Our goal was to analyze the effects of MitoQ (100 µM in drinking water) on the development and progression of heart failure induced by pressure overload after 14 weeks. The main findings are that pressure overload-induced heart failure in rats decreased cardiac function in vivo that was not altered by MitoQ. However, we observed a reduction in right ventricular hypertrophy and lung congestion in heart failure animals treated with MitoQ. Heart failure also decreased total mitochondrial protein content, mitochondrial membrane potential in the intermyofibrillar mitochondria. MitoQ restored membrane potential in IFM but did not restore mitochondrial protein content. These alterations are associated with the impairment of basal and stimulated mitochondrial respiration in IFM and SSM induced by heart failure. Moreover, MitoQ restored mitochondrial respiration in heart failure induced by pressure overload. We also detected higher levels of hydrogen peroxide production in heart failure and MitoQ restored the increase in ROS production. MitoQ was also able to improve mitochondrial calcium retention capacity, mainly in the SSM whereas in the IFM we observed a small alteration. In summary, MitoQ improves mitochondrial dysfunction in heart failure induced by pressure overload, by decreasing hydrogen peroxide formation, improving mitochondrial respiration and improving mPTP opening

Low mercury concentration produces vasoconstriction, decreases nitric oxide bioavailability and increases oxidative stress in rat conductance artery.

Mercury is an environmental pollutant that reduces nitric oxide (NO) bioavailability and increases oxidative stress, having a close link with cardiovascular diseases, as carotid atherosclerosis, myocardial infarction, coronary heart disease and hypertension. One of the main sites affected by oxidative stress, which develops atherosclerosis, is the aorta. Under acute exposure to low mercury concentrations reactive oxygen species (ROS) production were only reported for resistance vessels but if low concentrations of mercury also affect conductance arteries it is still unclear. We investigated the acute effects of 6 nM HgCl(2) on endothelial function of aortic rings measuring the reactivity to phenylephrine in rings incubated, or not, with HgCl(2) for 45 min, the protein expression for cyclooxygenase 2 (COX-2) and the AT1 receptor. HgCl(2) increased Rmax and pD2 to phenylephrine without changing the vasorelaxation induced by acetylcholine and sodium nitroprusside. Endothelial damage abolished the increased reactivity to phenylephrine. The increase of Rmax and pD2 produced by L-NAME was smaller in the presence of HgCl(2). Enalapril, losartan, indomethacin, furegrelate, the selective COX-2 inhibitor NS 398, superoxide dismutase and the NADPH oxidase inhibitor apocynin reverted HgCl(2) effects on the reactivity to phenylephrine, COX-2 protein expression was increased, and AT1 expression reduced. At low concentration, below the reference values, HgCl(2) increased vasoconstrictor activity by reducing NO bioavailability due to increased ROS production by NADPH oxidase activity. Results suggest that this is due to local release of angiotensin II and prostanoid vasoconstrictors. Results also suggest that acute low concentration mercury exposure, occurring time to time could induce vascular injury due to endothelial oxidative stress and contributing to increase peripheral resistance, being a high risk factor for public health

(A, B) The effect of indomethacin (Indo, 10 µM), on the concentration-response curves for phenylephrine in aortic rings in control (CT) conditions or HgCl2.

<p>Results (mean±SEM) are expressed as a percentage of the response to 75 mmol/l KCl. *<i>P</i><0.05 by ANOVA. Number of animals used in parentheses. (C) Differences in the area under the concentration-response curve (dAUC) in aortic rings cultured in the presence of indomethacin (10 µM) under control (CT) conditions and after acute incubation with mercury HgCl₂. *<i>P</i><0.05 by Student’s <i>t</i>-test.</p

Parameters of maximal response (Emax, mmHg) and sensitivity (pD2) of dose-response curves to phenyleprine in the aorta, before (E+) and after (E-) endothelial damage and after NG-nitro-L-arginine methyl ester (L-NAME, 100 µM) incubation, in the presence (HgCl2 E+) and absence of mercury chloride (E- HgCl2).

<p>Results are expressed as means ± SEM of the no. of animals shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049005#pone-0049005-g001" target="_blank">Figs. 1</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049005#pone-0049005-g002" target="_blank"></a><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049005#pone-0049005-g003" target="_blank">3</a>. P<0.05 vs. CT (E+) (*).</p

(A,B) The effects of enalapril (10 µM) and (C,D) losartan (10 µM) on the concentration-response curves for phenylephrine and (E) densitometric analysis of the western blot for AT₁ in aortic rings in control (CT) conditions or HgCl2.

<p>Results (mean±SEM) are expressed as a percentage of the response to 75 mmol/l KCl. *<i>P</i><0.05 by ANOVA. (E) Densitometric analysis of the western blot for angiotensin receptor 1 (AT1) protein expression in aortic rings cultured in the absence (CT) of HgCl₂ and after acute incubation with HgCl₂. *<i>P</i><0.05 by Student’s <i>t</i>-test. Number of animals used in parentheses. Representative blots are also shown.</p

The effect of apocynin (0.3 mM) on the concentration-response curves for phenylephrine in aortic rings in control (CT) conditions or HgCl2 (A,B).

<p>Results (mean±SEM) are expressed as a percentage of the response to 75 mmol/l KCl. *<i>P</i><0.05 by ANOVA. Number of animals used in parentheses. (C) Differences in the area under the concentration-response curve (dAUC) in aortic rings cultured the presence and absence apocynin (0.3 mM), under control (CT) conditions or HgCl₂. *<i>P</i><0.05 by Student’s <i>t</i>-test.</p

The effect of L-NAME (100 µM) on the concentration-response curves for phenylephrine in aortic rings in control (CT) conditions or HgCl2 (A,B).

<p>Results (mean±SEM) are expressed as a percentage of the response to 75 mmol/l KCl. *<i>P</i><0.05 by ANOVA. Number of animals used in parentheses. (C) Differences in the area under the concentration-response curve (dAUC) for aortic rings incubated in the presence and absence of L-NAME in controls (CT) or HgCl₂. *<i>P</i><0.05 by Student’s <i>t</i>-test.</p

The effect of endothelium removal (E-) on the concentration-response curves for phenylephrine in aortic rings in control (CT) conditions or HgCl2 (A,B).

<p>Results (mean±SEM) are expressed as a percentage of the response to 75 mmol/l KCl. *<i>P</i><0.05 by ANOVA. Number of animals used in parentheses. (C) Differences in area under the concentration-response curve (dAUC) in the presence and absence of the endothelium of aortic rings in control (CT) conditions or HgCl₂. *<i>P</i><0.05 by Student’s <i>t</i>-test.</p