Reduction of no-reflow and reperfusion injury with the synthetic 17β-aminoestrogen compound Prolame is associated with PI3K/Akt/eNOS signaling cascade

Abstract

A high proportion of primary percutaneous coronary interventions performed in the setting of acute myocardial infarction, concur with inadequate myocardial perfusion at the microvascular level. This phenomenon, known as "no-reflow" contributes to reperfusion injury, poor prognosis and to unfavorable clinical outcome. In this study, we evaluated the hypothesis that the synthetic 17β-aminoestrogen Prolame, may confer cardioprotection and prevent against no-reflow. In an open-chest model of 30-min ischemia and 90-min reperfusion, male Wistar rats were randomly assigned to different groups: Control, Prolame, Prolame followed by the nitric oxide synthase inhibitor (L-NAME), and 17β-estradiol. Areas of risk, infarct size and no-reflow were determined by planimetry with triphenyltetrazolium chloride and thioflavin-S stains. Structural damage of the vasculature was measured as capillary compression in clarified tissue after intra-atrial injection of Microfil. Hemodynamic function was obtained at the end of stabilization, ischemia and reperfusion; nitric oxide (NO·) content was determined indirectly using the Griess reaction. Activation of the eNOS signaling cascade was determined by western blot. Prolame reduced the infarcted area, decreased the zones of no-reflow and capillary compression by activating the PI3K/Akt/eNOS signaling pathway in correlation with NO· increase. Prolame also activated endothelial cells augmenting NO· production, which was inhibited by ICI182780 (a selective estrogen receptor down-regulator), supporting the notion that the cardioprotective effect of Prolame involves the preservation of endothelium through the activation of estrogen receptor downstream signaling. Our results provide evidence that Prolame has potential therapeutic application in patients with AMI, as it prevents from both vascular and cardiac tissue damage.

Empowering Adult Stem Cells for Myocardial Regeneration V2.0

“…In MSCs, Bcl-2 has been engineered to activate survival pathways capable of suppressing hypoxia-induced apoptosis [125], VEGF and Ang1 for the promotion and formation of new blood vessels [126], survivin to increase cellular survival after introduction into the damaged tissue [127] and the stem cell homing factor SDF-1 [128]. In CPCs, genetic modified targets include nuclear AKT [129], PIM-1 [130–132], ILK [133], nucleostemin [134], notch [135] and beta-adrenergic tolerance through 6-betaARKct [136]. PIM-1, a pro-survival and proliferation gene kinase, has been used to enhance CPCs with demonstrated long-term engraftment, increased cardiac function and reduced fibrotic scar as compared to regular CPCs or placebo in both small [130] and large animal models [132].…”

Neuroprotective effect of nicorandil through inhibition of apoptosis by the PI3K/Akt1 pathway in a mouse model of deep hypothermic low flow

“…Studies have shown that the PI3K/ Akt pathway reduces I/R injury upon its activation via opening of the mitoK ATP channel, where it radiates key effectors of the mitochondrial apoptosis pathway, including Bcl-2, Bax, and glycogen synthase kinase-3beta, and ultimately reduces the I/R injury [4,18,24]. Additionally, NO has been shown to induce the activation of PI3K/Akt signaling pathway [13] and many studies have demonstrated its protective effects following I/R injury in animal models [11,34]. However, the precise mechanisms underlying the protective effects of nicorandil against I/R injury during DHLF are not well understood.…”

Heart Rate Reduction With Ivabradine Protects Against Left Ventricular Remodeling by Attenuating Infarct Expansion and Preserving Remote‐Zone Contractile Function and Synchrony in a Mouse Model of Reperfused Myocardial Infarction

“…Recently, Gent and colleagues showed that mice given lifetime ivabradine treatment had a significantly longer lifespan than untreated mice, though they could not determine whether the longevity was secondary to heart rate reduction or to potential pleiotropic effects of ivabradine 43. The authors hypothesized that reduced reactive oxygen species formation, either because of heart rate reduction or a direct action of ivabradine, would be mechanistically consistent with greater longevity, particularly as mice die mostly from cancer and not from cardiovascular disease, where the benefit from heart rate reduction would be more direct.…”