Repeated Non-Invasive Limb Ischemic Preconditioning Confers Cardioprotection Through PKC-ε/STAT3 Signaling in Diabetic Rats

Background/Aims: Protein kinase C(PKC)-epsilon activation is a mechanism of preconditioning cardioprotection but its role in repeated non-invasive limb ischemic preconditioning (rNLIP) mediated cardioprotection against myocardial ischemia/reperfusion (I/R) injury in diabetes is unknown. Methods: Eight-week streptozotocin-induced diabetic and non-diabetic Sprague-Dawley rats were subjected to I/R without or with rNLIP. In vitro, H9C2 cells were cultured with high glucose (HG) and subjected to hypoxia/re-oxygenation (H/R) without or with PKC-epsilon or STAT3 gene knock-down in the absence or presence of remote time hypoxia preconditioning (HPC). Results: Diabetic rats displayed larger post-ischemic myocardial infarct size and higher troponin-I release with concomitant cardiac PKC-epsilon overexpression and activation manifested as increased membrane translocation, while phosphorylated STAT3 (p-STAT3) and Akt (p-Akt) were lower compared to non-diabetic rats (all P<0.05). rNLIP reduced infarct size in both non diabetic and diabetic rats. rNLIP reduced post-ischemic cardiac PKC-epsilon activation in diabetic while increased PKC-epsilon activation in non-diabetic rats, resulting in increased cardiac p-STAT3 and p-Akt. In H9C2 cells, HG increased PKC-epsilon expression and exacerbated post-H/R injury, accompanied with reduced p-STAT3 and p-Akt, which were all reverted by HPC. These HPC protective effects were abolished by either PKC-epsilon or STAT3 gene knock-down, except that PKC-epsilon gene knock-down reverted HG and H/R-induced reduction of p-STAT3. Conclusion: rNLIP attenuates diabetic heart I/R injury by mitigating HG-induced PKC-epsilon overexpression and, subsequently, activating STAT3. (C) 2018 The Author(s) Published by S. Karger AG, Basel