Insulin Postconditioning Reduces Infarct Size in the Porcine Heart in a Dose-Dependent Manner

Abstract

Insulin postconditioning reduced infarct size in the in vivo pig heart, but the beneficial effects were restricted to the highest dose, which is limited by side effects and can only be given to nonfasted animals. The finding challenges successful general use of insulin in the treatment of reperfusion injury in clinical acute myocardial infarction.

Tongxinluo attenuates reperfusion injury in diabetic hearts by angiopoietin-like 4-mediated protection of endothelial barrier integrity via PPAR-α pathway

“…Betulinic acid from Semen Ziziphi Spinosae possesses the effects of anti-oxidization by inhibiting reactive oxygen species (ROS) production and increasing the activities of SOD and CAT [ 31 ], anti-apoptosis by upregulating Bcl-2 and downregulating Bax and caspase-3 via the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (Akt) pathway [ 32 ], and anti-inflammation by decreasing the levels of IL-6, IL-1β, and TNF-α through the 5'-AMP-activated protein kinase (AMPK)/ nuclear factor (NF)-κB/ transcription factor Nrf2 pathway [ 31 ]. Melatonin from Periostracum cicadae, and scolopendra and Semen Ziziphi Spinosae, has the ability of anti-oxidization by scavenging free radicals and ROS, activating antioxidant defense enzymes, and increasing NO bioavailability [ 26 , 33 , 34 ], anti-inflammation by reducing the expression of P-selectin and ICAM, suppressing NFκB translocation into the nucleus [ 33 ], and decreasing endoplasmic reticulum stress [ 35 ], anti-apoptosis by up-regulating Bcl-xl and eNOS and down-regulating Bax, nNOS, and iNOS [ 36 ], mitochondria-protection by inhibiting the mitochondrial permeability transition pore (mPTP), activating uncoupling proteins (UCPs), reducing mitochondrial fission and elevating their fusion, promoting mitophagy, and improving homeostasis of mitochondria [ 34 ], and these effects are probably mediated by the Akt pathway [ 37 ].…”

“…For diabetes patients receiving reperfusion therapy, insulin is the preferred anti-diabetic drug, as it not only lowers the level of blood glucose but also decreases myocardial I/R injury by reducing myocardial apoptosis [ 36 , 38 ]. In our present study, we as well demonstrated the microvascular-protection effect of insulin in I/R-injured diabetic hearts.…”

“…In our present study, we as well demonstrated the microvascular-protection effect of insulin in I/R-injured diabetic hearts. The mechanism of insulin attenuates myocardial I/R injury involves improving energy metabolism via increasing glucose uptake [ 39 ], and lowering circulating free fatty acids [ 36 ]. Besides, studies have demonstrated that insulin maintained the perfusion of microvasculature in a nitric oxide (NO)–dependent manner [ 40 ], enhanced the expression of VE-cadherin and β-catenin in human fetoplacental vessels from pregnancies with diabetes [ 41 ], protected endothelial barrier function by suppressing endothelial contractile machinery and strengthening cell-cell adhesions through PI3K/Akt- and NO/cGMP-induced Rac1 activation [ 42 ].…”

The role of PI3Kα isoform in cardioprotection

“…In our study, we have used insulin as the PI3Kα canonical activator [ 8 , 27 ]. There is a wealth of evidence demonstrating that insulin mimics the IPC stimulus by activating the RISK pathway, therefore, conferring protection against IRI both in vitro and in vivo through the PI3K–Akt kinase cascade [ 22 , 23 , 46 ]. In the swine model, insulin postconditioning has recently been shown to reduce myocardial IS in a dose-dependent manner [ 46 ].…”

“…There is a wealth of evidence demonstrating that insulin mimics the IPC stimulus by activating the RISK pathway, therefore, conferring protection against IRI both in vitro and in vivo through the PI3K–Akt kinase cascade [ 22 , 23 , 46 ]. In the swine model, insulin postconditioning has recently been shown to reduce myocardial IS in a dose-dependent manner [ 46 ]. Not surprisingly, we found insulin to be protective in our models, which we confirm to specifically be mediated via PI3Kα.…”