Molecular chaperone, HSP60, and cytochrome P450 2E1 co‐expression in dilated cardiomyopathy

Abstract

Physiological stresses (heat, hemodynamics, genetic mutations, oxidative injury and myocardial ischemia) produce pathological states in which protein damage and misfolded protein structures are a common denominator. The specialized proteins family of antistress proteins - molecular chaperons (HSPs) - are responsible for correct protein folding, dissociating protein aggregates and transport of newly synthesized polypeptides to the target organelles for final packaging, degradation or repair. They are inducible at different cell processes such as cell division, apoptosis, signal transduction, cell differentiation and hormonal stimulation. HSPs are involved in numerous diseases including cardiovascular pathologies, revealing changes of expression and cell localization. We studied the possible changes in expression level of abundant mitochondrial chaperon Hsp60 and main human cytochrome P450 monooxygenase (2E1 isoform) at dilated cardiomyopathy (DCM) progression at the end stage of heart failure using Western blot analysis. The ischemic and normal humans' hearts were studied as control samples. We observed the decrease of Hsp60 level in cytoplasmic fraction of DCM- and ischemia-affected hearts' left ventricular and significant increase of Hsp60 in mitochondrial fractions of all hearts investigated. At the same time we detected the increase of P450 2E1 expression level in ischemic and dilated hearts' cytoplasmic fractions in comparison with normal myocardium and no detectable changes in microsomal fractions of hearts investigated which could be linked with increased level of oxidative injury for DCM heart muscle. In addition, all the changes described are accompanied by significant decrease of ATPase activity of myosin purified from DCM-affected heart in comparison with normal and ischemic myocardia as well. The data obtained allow us to propose a working hypothesis of functional link between antistress (HSPs) and antioxidative (cytochromes) systems at DCM progression.

Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT R141W Dilated Cardiomyopathy Transgenic Mice

“…[47][48][49][50] Thus, it is possible that hypoxemia in a state of cardiomyopathy triggers the formation of acetone, which then induces CYP2E1 to enhance the metabolism of endogenous ketones to meet the energy demand of the heart. The expression of CYP2E1 increases significantly in heart diseases, [13][14][15][16][17] and here we found that the expression of CYP2E1 also increased in ADR-induced DCM heart and Lmna E82K DCM mice ( Figure 1A and 1B). The previous reports and our results suggest that the upregulation of CYP2E1 might be an important molecular event to meet the energy demand in diseased hearts.…”

“…[10][11][12] The expression level of CYP2E1 increases significantly in heart tissues in humans under ischemia; mice, rats, and dogs with dilated cardiomyopathy (DCM); and spontaneously hypertensive rats. [13][14][15][16][17][18] The overexpression of CYP2E1 is associated with several cellular markers of oxidative stress, as well as with decreased viability as a result of both necrosis and apoptosis. [19][20][21][22] Oxidative stress and apoptosis in myocytes play important roles in the pathogenesis of cardiovascular diseases, such as ischemic heart disease, atherosclerosis, cardiomyopathy, and heart failure.…”

Chronic exposure to ambient particulate matter alters cardiac gene expression patterns and markers of oxidative stress in rats

“…Cyp2e1 activity may be an important mediator of oxidative stress response in the heart. Cyp2e1 activity is elevated in ischemic hearts and in hearts with dilated cardiomyopathy (Sidorik et al 2005). Lipid peroxidation in cardiomyocytes treated with acetaldehyde (a component of ambient particles) is reduced by the Cyp2e1 inhibitor, diallyl sulfide (Aberle and Ren 2003).…”

Impact of cigarette smoke exposure on the expression of cardiac hypertrophic genes, cytochrome P450 enzymes, and oxidative stress markers in rats

“…ed cardiomyopathy than that in healthy human hearts (Sidorik et al, 2005). The physiological importance of these enzyme emerge from their ability to metabolize arachidonic acid to various cardiotoxic metabolites, particularly hydroxyeicosatetraenoic acid (HETEs) (Elbekai and El-Kadi, 2006).…”