metallothionein and Heart-Failure

Cardiotoxicity is a serious complication of anticancer therapy by anthracycline antibiotics. Except for intercalation into DNA/RNA structure, inhibition of DNA-topoisomerase and histone eviction from chromatin, the main mechanism of their action is iron-mediated formation of various forms of free radicals, which leads to irreversible damage to cancer cells. The most serious adverse effect of anthracyclines is, thus, cardiomyopathy leading to congestive heart failure, which is caused by the same mechanisms. Here, we briefly summarize the basic types of free radicals formed by anthracyclines and the main processes how to scavenge them. From these, the main attention is paid to metallothioneins. These low-molecular cysteine-rich proteins are introduced and their functions and properties are reviewed. Further, their role in detoxification of metals and drugs is discussed. Based on these beneficial roles, their use as a new therapeutic agent against oxidative stress and for cardioprotection is critically evaluated with respect to their ability to increase chemoresistance against some types of commonly used cytostatics.

Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Cardiomyopathies; Cardiotonic Agents; Drug Resistance, Neoplasm; Free Radical Scavengers; Free Radicals; Heart Failure; Humans; Metallothionein; Neoplasms; Oxidative Stress

Left ventricular assist devices (LVAD) are used to "bridge" patients with end-stage heart failure until transplantation of a donor heart can be performed ("bridge to transplantation"). However, LVAD support sporadically results in improved cardiac function, and heart transplantation is not necessary even after removal of LVAD in a subset of patients ("bridge to recovery"). Additionally, LVAD appears to be an optional treatment alternative to heart transplantation in patients with contraindication for organ replacement ("destination therapy"). The underlying process has descriptively been termed "reverse remodeling". The molecular basis remains incompletely understood at present, however, some mechanisms have been identified in the past. Alterations of several molecular pathways are involved in the development of chronic heart failure. Some of the pathways appear to be reversible and have been shown to be regulated by LVAD treatment. LVAD lead to lowered cardiac pressure and volume overload followed by decreased ventricular wall tension, reduction of cardiomyocyte hypertrophy, improved coronary perfusion and a decrease of chronic ischemia in the myocardium. Improved coronary flow and myocardial perfusion as well as decreased ventricular wall tension may serve as a possible explanation for changes of the molecular systems involved in the development of chronic cardiac insuffiency. This review focuses on the roles of apoptosis, heme-oxygenase-1 (HO-1), Metallothionein (MT) and the transcription factor NFkkappaB in chronic heart failure after mechanical circulatory support.

Topics: Apoptosis; Heart Failure; Heart Function Tests; Heart Transplantation; Heart-Assist Devices; Heme Oxygenase-1; Humans; Metallothionein; NF-kappa B; Ventricular Dysfunction, Left

The antioxidant function of metallothionein (MT) was first suggested in the early 1980s. Studies in vitro have revealed that MT reacts directly with reactive oxygen species, including superoxide and hydroxyl radicals and hydrogen peroxide. These reactions have never been demonstrated in intact animal studies. Nevertheless, both pharmacologic and genetic studies have shown that MT functions in protection against oxidative injury in vivo. In particular, the antioxidant function of MT in the heart has been explored extensively. The data gathered from recent studies using a cardiac-specific, MT-overexpressing transgenic mouse model have provided direct evidence to support this physiological role of MT. Under acute and chronic oxidative stress conditions such as treatment with doxorubicin, ischemia-reperfusion, and dietary copper restriction, MT-overexpressing transgenic mouse hearts displayed a marked resistance to the injurious consequences, including biochemical, pathological, and functional alterations. This protective action of MT correlates with its inhibition of reactive oxygen species-induced lipid peroxidation. A critical elucidation of the mechanism of action of MT as an antioxidant in vivo remains to be achieved. However, the combination of recent understanding of the zinc cluster structure of MT and novel molecular genetic approaches has provided the basis for further advancement in this field.

Topics: Animals; Antioxidants; Doxorubicin; Heart; Heart Failure; Humans; Metallothionein; Mice; Myocardial Reperfusion Injury; Myocardium; Oxidative Stress

Pulmonary hypertension (PH) is defined as elevated mean pulmonary artery pressure secondary to e.g. congenital heart disease and chronic obstructive pulmonary disease. It elevates right ventricular afterload that eventually leads to cor pulmonale and right heart failure. Experimental research has shown that cardioprotective strategies may improve morbidity and reduce mortality in PH patients. PH and consequent right heart failure are underpinned by dysregulated mitochondrial dynamics, and therefore mitochondrial regulators may be targeted as cardioprotective agents in PH. Mitochondrial regulators such as the metallothioneins (MTs) confer cardioprotection against several forms of heart/lung disease. Furthermore, MT expression is up or downregulated in biopsies or blood from patients with PH. However, despite the overwhelming evidence that MT has potential as cardioprotective agents in PH, MT-induced cardioprotection has not been tested in experimental models of PH. Therefore, it is necessary to evaluate the attributes of MTs that make them candidates for cardioprotection in PH. The hypothesis presented in this paper is that upregulation of cardiac MTs can confer cardioprotection in PH and associated right ventricular remodelling. Mainly due to their ability to detoxify the myocardium of excess heavy metals, scavenging of free radicals and modulation of mitochondrial dynamics. These processes are instrumental in the development of PH and right ventricular remodelling. With this hypothesis we propose that the upregulation of cardiac MTs can confer cardioprotection in PH by detoxifying the myocardium of heavy metals and improving cardiac mitochondrial efficiency (i.e. reducing ROS, reducing oxidative stress, and improving antioxidant capacity and improving mitochondrial respiration).

Topics: Heart; Heart Failure; Heart Ventricles; Humans; Hypertension, Pulmonary; Metallothionein

We examined the distribution of metallothionein (MT), a stress-inducible protein, and the cardiomyocyte diameter in human hearts after left-ventricular assist device (LVAD) support.. Remodeling in end-stage heart failure is characterized by myocyte hypertrophy and alterations of several inducible proteins. LVADs used as a bridge to cardiac transplantation unload the left ventricle and may lead to a reversal of the remodeling, but little is known about the pathophysiology of this process.. The immunoreactivity for MT and the cardiomyocyte diameter was analyzed in left-ventricular tissue specimens of 17 patients with end-stage heart failure before and after LVAD support.. MT positive cells were mainly located sub-endocardially in vacuolized cardiomyocytes and in small vessels throughout the myocardium. During LVAD support, MT-positive myocytes decreased in the sub-endocardial (p < 0.008) and sub-epicardial region (p < 0.003), MT-positive vessels decreased similarly (p < 0.003). Cardiomyocyte diameter decreased significantly only in the sub-endocardium (p < 0.03). Hearts of patients supported longer than 88 days (= median) showed substantially lower MT reactivity at the time of LVAD explantation as compared to patients supported less than 88 days.. Our results suggest that unloading of the left ventricle during prolonged LVAD support leads to regression of cellular hypertrophy and a decrease of MT expression. The preferential reduction of MT-positive vacuolized cardiomyocytes in the sub-endocardium is comparable with the concept of greatest reduction of wall stress in this area of the myocardium and may be due to the improvement of myocardial blood flow and the energy balance.

Topics: Adult; Antibodies, Monoclonal; Biomarkers; Cell Size; Foreign-Body Reaction; Heart Failure; Heart-Assist Devices; Humans; Metallothionein; Middle Aged; Myocardium; Severity of Illness Index; Ventricular Remodeling