The first minutes of reperfusion: a window of opportunity for cardioprotection

Abstract

During the past decade, the understanding has grown that control of the conditions of reperfusion is critical for salvaging ischemic-reperfused myocardium. The first few minutes of reperfusion constitute a critical phase, as here lethal tissue injury in addition to that already developed during ischemia may be initiated. The identification of the mechanisms of reperfusion-induced cell death opens a new window of opportunity for cardioprotection in the clinic. Development of cardiomyocyte hypercontracture is a predominant feature of reperfusion injury. We and others have shown that control of hypercontracture in reperfusion reduces the extent of tissue injury. On the cellular level, it was shown that reperfusion-induced hypercontracture might either originate from a rigor-type mechanism, when energy recovery proceeds very slowly, or from Ca2+ overload, when energy recovery is rapid but cytosolic Ca2+ load is high. These two mechanisms can be influenced by various interventions that either connect with cytosolic Ca2+ control or myofibrillar Ca2+ sensitivity or with mitochondrial energy production. These experimental approaches will hopefully lead to novel strategies for clinical cardioprotection during the early phase of reperfusion.

Overexpression of TRPC3 increases apoptosis but not necrosis in response to ischemia-reperfusion in adult mouse cardiomyocytes

“…Although a number of Ca 2ϩ entry pathways have been implicated in mediating cardiomyocyte Ca 2ϩ overload following I/R, including the Na ϩ /Ca 2ϩ exchanger and the L-type Ca 2ϩ channel (4,8,32), there is still considerable controversy as to which pathways are critical in mediating this process. In cardiomyocytes, angiotensin-and phenylephrine-induced CCE is inhibited by glucosamine and SKF-96365 (12,27); glucosamine also protected the isolated perfused heart from calcium overload induced by the calcium paradox (20).…”

“…An increase in cytosolic Ca 2ϩ plays a critical role in initiating cardiomyocyte apoptosis and necrosis that occur in response to ischemia-reperfusion (I/R) (4,6). Although a number of Ca 2ϩ entry pathways, including the Na ϩ /Ca 2ϩ exchanger and the L-type Ca 2ϩ channel, have been implicated in mediating cardiomyocyte Ca 2ϩ overload (4,6,32), there is little consensus as to which pathways are critical in mediating this process. We have identified a capacitative calcium entry (CCE) or store-operated calcium entry pathway in neonatal and adult rat cardiomyocytes (12,13) that not only influences the response to hypertrophic stimuli but may also play a role in mediating Ca 2ϩ overload in the heart (20).…”

The Protective Effect of Epigallocatechin-3 Gallate on Ischemia/Reperfusion Injury in Isolated Rat Hearts: Anex vivoApproach

“…The early phase of reperfusion represents an important target for strategies to protect ischemic-reperfused myocardium [19]. Reperfusion injuries could be attenuated by intervention at the time of reperfusion [20].…”

Revisiting Kadenbach: Electron flux rate through cytochrome c‐oxidase determines the ATP‐inhibitory effect and subsequent production of ROS

“…EGF, interleukins, TNF‐α) to receptors of signaling cascades through NADPH oxidases at the plasma membrane 33. They act on receptor tyrosine kinases, protein kinase C, or on mitogen‐activated protein kinases, such as those involved in signaling pathways of ERK1/2, JNK, or directly on transcription factors, in addition to leading to changes in calcium homeostasis, cellular pH or the degree of reduction of nucleotides (NADH/NAD+) and ATP content 23, 34, 35, 36. Otherwise, they appear in mitochondria at high membrane potential (Ψm >140 mV) values 37, 38.…”