Cellular Redistribution of Inducible Hsp70 Protein in the Human and Rabbit Heart in Response to the Stress of Chronic Hypoxia

Abstract

Many infants who undergo cardiac surgery have a congenital cyanotic defect where the heart is chronically perfused with hypoxemic blood. Infant hearts adapt to chronic hypoxemia by activation of intracellular protein kinase signal transduction pathways. However, the involvement of heat shock protein 70 in adaptation to chronic hypoxemia and its role in protein kinase signaling pathways is unknown. We determined expression of message and subcellular protein distribution for inducible (Hsp70i) and constitutive heat shock protein 70 (Hsc70) in chronically hypoxic and normoxic infant human and rabbit hearts and their relationship to protein kinases. In chronically hypoxic human and rabbit hearts message levels for Hsp70i were elevated 4-to 5-fold compared with normoxic hearts, Hsp70i protein was redistributed from the particulate to the cytosolic fraction. In normoxic infants Hsp70i protein was distributed almost equally between the cytosolic and particulate fractions. Hsc70 message and subcellular distribution of Hsc70 protein were unaffected by chronic hypoxia. We then determined if protein kinases influence Hsp70i protein subcellular distribution. In rabbit hearts SB203580 and chelerythrine reduced Hsp70i message levels, whereas SB203580, chelerythrine, and curcumin reversed the subcellular redistribution of Hsp70i protein caused by chronic hypoxia, with no effect in normoxic hearts, indicating regulation of Hsp70i message and subcellular distribution of Hsp70i protein in chronically hypoxic rabbit hearts is influenced by protein kinase C and mitogen-activated protein kinases, specifically p38 MAPK and JNK. We conclude the Hsp70 signal transduction pathway plays an important role in adaptation of infant human and rabbit hearts to chronic hypoxemia.

Overexpression of PrPCby Adenovirus-Mediated Gene Targeting Reduces Ischemic Injury in a Stroke Rat Model

“…In vivo chronic hypoxic injury also enhances the expression of Hsp70 (Rafiee et al, 2003). Previously, a close correlation between PrP C and Hsp70 was demonstrated (Jung et al, 2000(Jung et al, , 2002.…”

Heat Shock Proteins and Mitogen-activated Protein Kinases in Steatotic Livers Undergoing Ischemia-Reperfusion: Some Answers

“…HSP72 induction includes p38 MAPK (p38) and c-Jun N-terminal kinase (JNK) in heart in response to hypoxia. 11 HO-1 overexpression by p38 and JNK has been reported in cultures of hepatocytes, 12 isolated endothelial cells, 13 and experimental models of lung I/R. 14 The respective roles of HSPs and MAPKs in inducing the benefits of ischemic preconditioning on I/R injury in steatotic livers remain unclear.…”

“…In fact, the mechanisms involved in the beneficial effects of the two sources of NO might well be different. 53 Given the benefits of MAPK activation caused by preconditioning in hepatocytes and experimental models of perfused liver, 9,10 and the relationship between MAPKs and HSPs, [11][12][13][14] we posited that the increased HSP levels caused by preconditioning were mediated by MAPK activation. However, our results obtained with the pharmacological modulation of MAPKs, are in line with those reported in a study in transplantation from steatotic liver grafts indicating that JNK activation might be harmful to hepatocytes after reperfusion.…”

Sildenafil Citrate (Viagra) Induces Cardioprotective Effects after Ischemia/Reperfusion Injury in Infant Rabbits

“…Early surgical intervention is important to promote more normal development. Infants undergoing surgery for congenital heart disease are at risk for myocardial ischemia during cardiopulmonary bypass, circulatory arrest, or low-flow states (1). Less is known about the tolerance of the infant myocardium to ischemia compared with the adult, and cardiac reserves are more limited in the infant (2).…”