Cardioprotection 'Outside the Box' - The evolving paradigm of remote preconditioning
ABSTRACT Conventional ischemic preconditioning is the phenomenon whereby brief episodes of myocardial ischemia render the ischemic territory resistant to a subsequent, sustained ischemic insult. A growing body of evidence further indicates that brief ischemia applied in distant organs and tissues can also protect naïve, virgin myocardium from ischemic injury. In this review, we describe the initial observations that provided the impetus for the study of 'remote preconditioning', and summarize our current knowledge of the three facets of 'preconditioning at a distance' --intra-cardiac, inter-organ and transferred inter-cardiac preconditioning.
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ABSTRACT: Akt/protein kinase B is a well-known cell survival factor and activated by many stimuli including mechanical stretching. Therefore, we evaluated the cardioprotective effect of a brief mechanical stretching of rat hearts and determined whether activation of Akt through phosphatidylinositol 3-kinase (PI3K) is involved in stretch-induced cardioprotection (SIC). Stretch preconditioning reduced infarct size and improved post-ischemic cardiac function compared to the control group. Phosphorylation of Akt and its downstream substrate, GSK-3β, was increased by mechanical stretching and completely blocked by wortmannin, a PI3K inhibitor. Treatment with lithium or SB216763 (GSK-3β inhibitors) before ischemia induction mimicked the protective effects of SIC on rat heart. Gadolinium (Gd3+), a blocker of stretch-activated ion channels (SACs), inhibited the stretch-induced phosphorylation of Akt and GSK-3β. Furthermore, SIC was abrogated by wortmannin and Gd3+. In vivo stretching induced by an aorto-caval shunt increased Akt phosphorylation and reduced myocardial infarction; these effects were diminished by wortmannin and Gd3+ pretreatment. Our results showed that mechanical stretching can provide cardioprotection against ischemia-reperfusion injury. Additionally, the activation of Akt, which might be regulated by SACs and the PI3K pathway, plays an important role in SIC.Journal of Veterinary Science 09/2012; 13(3):235. DOI:10.4142/jvs.2012.13.3.235 · 1.14 Impact Factor
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ABSTRACT: Remote ischemic preconditioning (rIPC) with short episodes of ischemia and reperfusion (I/R) of an organ remote from the heart is a powerful approach to protect against myocardial I/R injury. The signal transduction pathways for the crosstalk between the remote site and the heart remain unclear in detail. To elucidate the role of circulating nitrite in cardioprotection by rIPC. Mice were subjected to 4 cycles of no-flow ischemia with subsequent reactive hyperemia within the femoral region and underwent in vivo myocardial I/R (30 min/5 min or 24 h). The mouse experiments were conducted using genetic and pharmacological approaches. Shear stress dependent stimulation of endothelial nitric oxide synthase (eNOS) within the femoral artery during reactive hyperemia yielded substantial release of nitric oxide (NO•), subsequently oxidized to nitrite and transferred humorally to the myocardium. Within the heart, reduction of nitrite to NO• by cardiac myoglobin (Mb) and subsequent S-nitrosation of mitochondrial membrane proteins reduced mitochondrial respiration, reactive oxygen species (ROS) formation and myocardial infarct size. Pharmacological and genetic inhibition of NO•/nitrite generation by eNOS at the remote site or nitrite bioactivation by Mb within the target organ abrogated the cardioprotection by rIPC. Transfer experiments of plasma from healthy volunteers subjected to rIPC of the arm identified plasma nitrite as a cardioprotective agent in isolated Langendorff mouse heart preparations exposed to I/R. Circulating nitrite derived from shear stress dependent stimulation of eNOS at the remote site of rIPC contributes to cardioprotection during I/R.Circulation Research 03/2014; 114(10). DOI:10.1161/CIRCRESAHA.114.303822 · 11.09 Impact Factor
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ABSTRACT: Background: Remote ischemic perconditioning (rPER) is the newest technique described to mitigate ischemia and reperfusion (IR) injury. Local postconditioning (POS) is also an effective technique for this purpose. It is uncertain if adding local POS to rPER provides superior liver protection, so we tested this hypothesis. Materials and methods: Twenty five Wistar rats were assigned into five groups: sham, IR, POS, rPER, and rPER + POS. Animals were subjected to liver ischemia for 60 min. POS consisted of four cycles of 5-min liver perfusion followed by 5-min liver ischemia (40 min total) after the major ischemic period. rPER consisted of four cycles of 5-min hindlimb ischemia followed by 5 min hindlimb perfusion contemporaneously to major liver ischemic period, during its last 40 min. After 2 h, median and left lobes were harvested for malondialdehyde and Trolox equivalent antioxidant capacity (TEAC) measurement, and blood for the measurement of serum transaminases. Results: All tissue conditioning techniques were able to reduce transaminases serum levels, having no differences among them. All tissue conditioning techniques were able to reduce hepatic tissue MDA level; however, only rPER + POS had higher values than SHAM. All tissue conditioning techniques also enhanced TEAC; however, only POS had lower TEAC than SHAM. Conclusions: rPER appears as the most promising technique to avoid IR injury. This technique reduced oxidative stress of cell membranes and lowered transaminases serum level. There was no additive protection when POS and rPER were held together.Journal of Surgical Research 05/2014; 192(1). DOI:10.1016/j.jss.2014.05.046 · 2.12 Impact Factor