Heat Shack Factor
Synthesis of heat shock -proteins
Degradation of abnormal proteins
Figure 24. Heat shock proteins constitute an endogenous defense system antagonizing protein unfolding or misfolding that occurs upon stress. They enhance cytoskeletal stability, inhibit apoptosis and increase NO synthesis. Ovcrcxpcssion of heat shock proteins increases cellular tolerance to ischemia and reperfusion injury.
ischemia and reperfusion.183 Ischemic preconditioning induced cardioprotection has been associated with accelerated «B-crystall in translocation and phosphorylation during the prolonged ischemia.184 Similarly, ischemic and isoproterenol preconditioning resulted in activation of p38 MAPK with subsequent induction of Hsp27. However, during the index ischemia, Hsp27 phosphorylation remained increased while p38 MAPK activation was attenuated.148 Accordingly, thyroxine induccd cardioprotection was associated with increased Hsp27 expression and acceleration of Hsp27 phosphorylation and translocation to the cytoskeleton upon ischemia.185
Hsp60 and HsplO are located predominantly in the mitochondria. Accumulation of unfolded proteins within the mitochondrial matrix results in transcriptional up regulation of genes encoding these proteins. Their ov«-expression in rat neonatal cells leads to protection associated with increased ATP recovery and preservation of complex III and IV activities in the mitochondria.IWi' A small amount of Hsp60 is also found in cytosol and forms a macromolecular complex with Bax and Bak but not with Bcl-2. Reduction of HspfiO levels by antisense oligonucleotides increases the unbound Bax, indicating an important role of the cytosolic Hsp60 in the process of apoptosis.197 Hypoxia results in dissociation of the Hsp60-Bax and translocation of Hsp60 to membrane and Bax to mitochondria, a process sufficient to trigger apoptosis.1SS
Hsp90 is an ATP dependent molecular chaperone involved in the folding and activation of various substrate proteins which include kinases and transcription factors such as HlF-la and HSF1. Furthermore, Hsp90 has a regulatory effect on steroid receptors. Figure 12. Steroid hormones via the interaction of HSF1 and Hsp90 regulate heat shock protein expression in adult rat cardiomyocytes.1™ Disruption of Hsp90 by gel dan am y-cin promotes HIF-1« degradation with marked reduction in both accumulation of the hypoxia -induced VEGF mRNA and hypoxia-dependent angiogenic activity.150 Hsp90 acts also as anti-apoplotic in concert with Hsp70. Evidence for a cardioprotective role of Iisp90 is provided by studies in rat neonatal cardiomyocytes showing that uroeortin induced cardioprotection is associated with increased expression of heat shock protein 90 in a MEK1/2 dependent pathway manner.191
Complex cell signaling pathways exist in the cell and are involved in growth, cell survival or cell death. Intracellular signaling is a transducer of adaptive and/or maladaptive responses of the cell to stress. Signals are transduced through kinase cascades to nucleus via transcription factors. Receptor and non receptor stimuli activate intracellular cascades. Several endogenous mediators such as catecholamines, acetylcholine, adenosine, angiotensin, endothelin, bradykinin or opioids released in myocardial ischemia and bound to G protein coupled receptors can mediate pro-survival or pro-death signaling. Non receptor stimuli such as nitric oxide (NO) and reactive oxygen species (ROS) also induce signaling which may be either beneficial or detrimental, depending on their amount. Protein kinase A and protein kinase C isoforms serve an important role in the adaptive response of the heart to ischemia and reperfusion. The role of PKA in ischemic tolerance remains elusive. Beneficial or detrimental effects are reported with PKA activation. PKCe and PKC6 have been mostly studied in relation to ischemia and reperfusion. PKCe has been linked to cardioprotection while PKC5 is shown to be either cardioprotective or detrimental. MAP kinases are activated during ischemia and/or reperfusion and their role in the adaptive response of the cell to ischemia has been intensively studied. ERK activation is associated with cardioprotection. JNK is pro-apoptotic and p38 MAPK can be either pro-survival or pro-apoptotic. Transient activation of p38 MAPK or JNK may be beneficial while sustained activation is detrimental. Activation of the PI3K/Akt pathway facilitates cell survival. Transcription factors, such as NF-kB, AP-1 or p53 are activated under ischemia and reperfusion and regulate the transcription of either survival or pro-death genes.
Lack of oxygen induces an adaptive response of the cell, a process that is largely controlled by a transcription factor known as hypoxia inducible factor (HIF-1). HIF-la activation leads to the transcription of genes encoding for erythropoietin, vascular endothelial growth factor (VEGF), insulin growth factor, glucose transporters and glycolytic enzymes. This HIFcx regulated gene program allows cell survival under conditions of low oxygen tension.
Heat shock proteins are involved in an endogenous defense mechanism which antagonizes protein unfolding or misfolding occuring upon stress. They enhance cytoskel-etal stability, inhibit apoptosis and increase NO synthesis. Overexpession of heat shock proteins in the myocardium increases ischemic tolerance.
In 1986 Murry, Jennings and Reimer made the observation that brief episodes of ischemia and reperfusion have the ability to adapt the heart to a subsequent prolonged episode of ischemia followed by reperfusion and this phenomenon is known as ischemic preconditioning.192 This form of adaptation consists of an early transient phase lasting hours (classic or early preconditioning) and a late phase, lasting 1 to 3 days (delayed
Zeio-flow. global Rapwfugon
Zeio-flow. global Rapwfugon
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