A miokardium intracelluláris kalcium homeosztázisa: Iszkémiás és kardiomiopátiás változások
Cardiac contractility is dependent upon the precise regulation of intracellular Ca2+i cycling, i.e. the Ca2+ i transient. In the present study disturbances of Ca2+ i handling in ischemic/reperfused heart after heat shock (HS) treatment and in doxorubicin (DOX) induced cardiomyopathy have been studied.
Over the past two decades, numerous studies have shown that HS preconditioning enhances the tolerance of the heart against ischemia/reperfusion insult. One of the features of ischemia/reperfusion-induced cardiac injury is the persistent increase of intracellular free Ca2+ level. Experimental data on Ca2+i handling in the ischemic/reperfused heart after HS treatment are, however, scarce. The available information mainly pertains alterations in SR calcium uptake and is contradictory. No experimental data regarding HS preconditioning and Ca2+i handling during ischemia/reperfusion have been obtained in isolated cardiomyocytes or perfused heart preparations, hence one of the main aims of the present study was, therefore, to determine the effect of in vivo HS pretreatment on Ca2+i handling in the intact ischemic/reperfused rat heart in relation to contractile performance and to disclose the nature of the alterations in Ca2+ release and sequestration processes, if there is.
Development of cardiomyopathy is multifactorial. However, it appears that oxidative and nitrosative stress---such as induced by DOX---plays a clear role in this process. Doxorubicin undergoes redox cycling to generate free radicals that are responsible for mediating the various cytopathologies associated. One of the more recently identified pathways of doxorubicin cardiotoxicity is related to poly(ADP ribose) polymerase (PARP) activation. When activated by DNA single-strand breaks, PARP initiates an energy consuming cycle slowing the rate of glycolysis and mitochondrial respiration eventually leading to cellular dysfunction and death. Very little is known however how these processes affect Ca2+i handling of the cardiomyocyte, prompting the secondary aim of the present study.
In the first part of our study we have shown for the first time in intact hearts "in vitro" that heat shock pretreatment prevents a further increase in end-diastolic Ca2+i after an ischemia/reperfusion insult and, hence, mitigates post-ischemic calcium overload. Our results also suggest that improved postischemic myocardial performance in response to HS pretreatment is at least partly due to a relatively preserved sensitivity of the myocardial contractile machinery towards Ca2+. However, delineation of the precise mechanisms responsible for the observed phenomena needs further experimental work.
In the second part of this study we made the following observations (1) demonstration of an increase in end-diastolic calcium levels in doxorubicin-treated hearts; (2) development of a decline in calcium sensitivity of the contractile machinery in the diseased hearts; (3) the enhanced susceptibility of the doxorubicin-treated hearts towards a subsequent acute oxidative stress and (4) the protective effects of PARP inhibitor, strongly suggesting that activation of the nuclear enzyme PARP is involved in the functional alterations of the doxorubicin-treated heart. Overall, the results of the current study are consistent with the notion that reactive oxidant species and the PARP pathway play a pathogenetic role in the development of doxorubicin induced cardiac dysfunction. Normalization of cellular calcium handling appears to be an additional mode of the cardio protective effects of PARP inhibitors.
Anatomy & physiology
0719: Anatomy & physiology