Journal of molecular and cellular cardiology
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J. Mol. Cell. Cardiol. · Jul 2008
Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts--role of late sodium current and intracellular ion accumulation.
The goal of this study was to test the hypothesis that the novel anti-ischemic drug ranolazine, which is known to inhibit late I(Na), could reduce intracellular [Na(+)](i) and diastolic [Ca(2+)](i) overload and improve diastolic function. Contractile dysfunction in human heart failure (HF) is associated with increased [Na(+)](i) and elevated diastolic [Ca(2+)](i). Increased Na(+) influx through voltage-gated Na(+) channels (late I(Na)) has been suggested to contribute to elevated [Na(+)](i) in HF. ⋯ In summary, ranolazine reduced the frequency-dependent increase in diastolic tension without having negative inotropic effects on contractility of muscles from end-stage failing human hearts. Moreover, in rabbit myocytes the increases in late I(Na), [Na(+)](i) and [Ca(2+)](i) caused by ATX-II, were significantly blunted by ranolazine. These results suggest that ranolazine may be of therapeutic benefit in conditions of diastolic dysfunction due to elevated [Na(+)](i) and diastolic [Ca(2+)](i).
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J. Mol. Cell. Cardiol. · Jun 2008
ReviewLate sodium current inhibition as a new cardioprotective approach.
There is increasing evidence that the late sodium current of the sodium channel in myocytes plays a critical role in the pathophysiology of myocardial ischemia and thus is a potential therapeutic target in patients with ischemic heart disease. Ranolazine, an inhibitor of the late sodium current, reduces the frequency and severity of anginal attacks and ST-segment depression in humans, and unlike other antianginal drugs, ranolazine does not alter heart rate or blood pressure. In experimental animal models, ranolazine has been shown to reduce myocardial infarct size and to improve left ventricular function after acute ischemia and chronic heart failure. This article reviews published data describing the role of late sodium current and its inhibition by ranolazine in clinical and experimental studies of myocardial ischemia.
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J. Mol. Cell. Cardiol. · Feb 2008
Stimulation of mitochondrial biogenesis and autophagy by lipopolysaccharide in the neonatal rat cardiomyocyte protects against programmed cell death.
Adult rat cardiomyocytes in culture respond to sub-lethal doses of lipopolysaccharides (LPS) by activation of pathways including the production of TNF-alpha and increased apoptosis. We and others have demonstrated a protective phenotype for neonatal rat cardiomyocytes to LPS. Concentrations of LPS far exceeding those necessary to induce TNF-alpha release do not induce apoptosis in the neonatal cells, although these cells are fully capable or inducing apoptosis in response to multiple other stimuli. ⋯ Furthermore, inhibition of autophagy in the presence of LPS stimulates markers of apoptosis. Our data suggest that the protective response of neonatal cells to LPS is multi-faceted at the level of the mitochondrion. Viable cells replace dysfunctional mitochondria by mitochondrial biogenesis and the extent of the damage limited by the rapid removal of damaged organelles by the stimulation of autophagy.
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J. Mol. Cell. Cardiol. · Jan 2008
Caveolin-3 expression and caveolae are required for isoflurane-induced cardiac protection from hypoxia and ischemia/reperfusion injury.
Volatile anesthetics protect the heart from ischemia/reperfusion injury but the mechanisms for this protection are poorly understood. Caveolae, sarcolemmal invaginations, and caveolins, scaffolding proteins in caveolae, localize molecules involved in cardiac protection. We tested the hypothesis that caveolae and caveolins are essential for volatile anesthetic-induced cardiac protection using cardiac myocytes (CMs) from adult rats and in vivo studies in caveolin-3 knockout mice (Cav-3(-/-)). ⋯ Isoflurane-induced cardiac protection was abolished in Cav-3(-/-) mice (infarct size: 53.4%+/-6.1% vs. 53.2%+/-3.5%, P<0.01; troponin: 102.1+/-22.3 vs. 105.9+/-8.2 ng/ml, P<0.01). Isoflurane-induced cardiac protection is thus dependent on the presence of caveolae and the expression of caveolin-3. We conclude that caveolae and caveolin-3 are critical for volatile anesthetic-induced protection of the heart from ischemia/reperfusion injury.
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J. Mol. Cell. Cardiol. · Sep 2007
ReviewReverse remodeling during long-term mechanical unloading of the left ventricle.
A significant proportion of patients placed on long-term mechanical circulatory support for end-stage heart failure can be weaned from mechanical assistance after functional recovery of their native heart ("bridge to recovery"). The pathophysiological mechanisms implicated in reverse remodeling that cause a sustained functional myocardial recovery have recently become the subject of intensive research, expected to provide information with a view to accurately identify reliable prognostic indicators of recovery. In addition, this kind of information will enable changes in the strategy of myocardial recovery by modifying the duration and scale of the unloading regimen or by combining it with other treatments that promote reverse remodeling.