Oxidative Damage Precedes Nitrative Damage in Adriamycin-Induced Cardiac Mitochondrial Injury

Abstract

The purpose of the present study was to determine if elevated reactive oxygen (ROS)/nitrogen species (RNS) reported to be present in adriamycin (ADR)-induced cardiotoxicity actually resulted in cardiomyocyte oxidative/nitrative damage, and to quantitatively determine the time course and subcellular localization of these postulated damage products using an in vivo approach. B6C3 mice were treated with a single dose of 20 mg/kg ADR. Ultrastructural damage and levels of 4-hydroxy-2-nonenal (4HNE)-protein adducts and 3-nitrotyrosine (3NT) were analyzed. Quantitative ultrastructural damage using computerized image techniques showed cardiomyocyte injury as early as 3 hours, with mitochondria being the most extensively and progressively injured subcellular organelle. Analysis of 4HNE protein adducts by immunogold electron microscopy showed appearance of 4HNE protein adducts in mitochondria as early as 3 hours, with a peak at 6 hours and subsequent decline at 24 hours. 3NT levels were significantly increased in all subcellular compartments at 6 hours and subsequently declined at 24 hours. Our data showed ADR induced 4HNE-protein adducts in mitochondria at the same time point as when mitochondrial injury initially appeared. These results document for the first time in vivo that mitochondrial oxidative damage precedes nitrative damage. The progressive nature of mitochondrial injury suggests that mitochondria, not other subcellular organelles, are the major site of intracellular injury.

Phenylbutyrate, a histone deacetylase inhibitor, protects against Adriamycin-induced cardiac injury

“…In current studies of ADR cardiotoxicity, the single high dose model [33,34,48,49] and the low dose chronic model [50,51] are two widely used dosage models, which both provided valuable biological insights in of ADR-induced cardiac injury. For the single high dose model, the dosage, 20 mg/kg, is equivalent to a high dose single injection in cancer patients, such as patients with small cell lung cancer [52].…”

“…Thirty cardiomyocytes were photographed and analyzed for each mouse. Quantification of mitochondrial damage was performed following the strict criteria for mitochondrial injury and image analysis techniques as previously described [34]. Investigators performing morphometry were blinded as to the categories of the samples.…”

Characterization of a Degenerative Cardiomyopathy Associated with Domoic Acid Toxicity in California Sea Lions (Zalophus californianus)

“…28-60) that had the degenerative cardiomyopathy but excluded them from the study set (Nos. [1][2][3][4][5][6][7][8]. The condition of nonsuppurative polymyositis (T. S. Zabka, personal observation) began as an inflammatory lesion predominantly of lymphocytes, occasional neutrophils, and eventually histiocytes and plasma cells, with secondary segmental hyaline degeneration and necrosis of cardiomyocytes, but notably without cytoplasmic vacuolization.…”

“…24 The similarity in lesion morphology may be because the pathogenesis involves apoptotic pathways. 4 Doxorubicin toxicity was dependent on repeated dosing, has an insidious onset and variable latency period of 0-2.5 year (median 3-8 weeks), and becomes rapidly progressive with cardiac failure occurring within 1 week to 2.5 months after the final dose. 24 This is interesting in light of the sea lion cardiomyopathy in which the duration of the cardiac lesions did not necessarily correspond to the duration of the brain lesion, which was evident especially in animals with the acute to subacute cardiomyopathy.…”

Late cardiotoxicity of high-dose chemotherapy according to the modified NHL-BFM-90 program in adult patients with diffuse large B-cell lymphoma

“…Механизм КТ за-ключается в прямом повреждающем воздействии свобод-ных радикалов на кардиомиоциты [17], в способности связываться с сократительными белками миоцитов (что в дополнение к лизису миофибрилл может значительно снижать сократимость миокарда) [18], в повреждении ми-тохондрий [19] (что приводит к нарушению энергетиче-ских обменов в клетке). Отдаленная кардиотоксичность mNHL-BFM-90 у больных ДВККЛ На КТ циклофосфамида влияют общая доза, полу-ченная за курс, предлеченность антрациклинами, пред-шествующее облучение средостения.…”