Cardioprotective effect of zinc requires ErbB2 and Akt during hypoxia/reoxygenation.
Recent literature suggests that exogenous zinc can prevent ischemia reperfusion injury by activating phosphoinositide-3 kinase (PI3K)/Akt and by targeting the mitochondrial permeability transition pore (mPTP). It is known that ErbB2 expression promotes association and activation of PI3-kinase/Akt, resulting in growth and survival of cardiac myocytes. In this study, we found that zinc-induced ErbB2 protein expression and Akt activation are required for preventing reperfusion injury. Neonatal rat cardiac myocytes subjected to 8 h of hypoxia, followed by 16 h of reoxygenation induced cardiomyocyte apoptosis, as assessed by increased caspase-3 activity, annexin V staining and lowered MTT reduction and ATP levels. However, addition of zinc-pyrithione (ZPT) before onset of reoxygenation effectively lowered the apoptotic indices and restored the ATP levels. ZPT induced a significant increase in ErbB2 protein expression and Akt activation. Pretreatment with Hsp 90 inhibitor, geldanamycin or PI3-kinase inhibitor, wortmannin prevented the increase in ATP levels and abrogated the protective effect of zinc-pyrithione. Taken together, these data suggest that zinc prevents reperfusion injury by modulating the ErbB2 protein expression and Akt activation.
Viswanath
Kasi
K
Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA.
Bodiga
Sreedhar
S
Balogun
Victor
V
Zhang
Anita
A
Bodiga
Vijaya Lakshmi
VL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000860:Hypoxia; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism*
D009942:Organometallic Compounds; D010100:Oxygen; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D018719:Erb-b2 Receptor Tyrosine Kinases; C010423:pyrithione zinc