Substance P induces cardioprotection in ischemia-reperfusion via activation of AKT

Abstract

Accumulating evidence indicates that substance P is cardioprotective following ischemia-reperfusion primarily due to its potent coronary vasodilator actions. However, an anti-apoptotic effect of substance P has been observed in tenocytes following ischemia, which involved activation of the AKT pathway. This suggests the possibility that substance P also provides cardioprotection via direct actions to activate AKT in myocardial cells. The purpose of this study was to test the hypothesis that substance P attenuates ischemia-related cell death via direct effects on myocardial cells by activating cell survival pathways. Seven-week-old male Sprague-Dawley rats, anesthetized with intraperitoneal pentobarbital sodium (100 mg/kg), were used. The ability of substance P to prevent cellular damage was assessed following ischemia-reperfusion in an isolated heart preparation and in short-term hypoxia without reperfusion using a left ventricular tissue slice culture preparation. In addition, the NK-1 receptor and AKT involvement was assessed using the NK-1 receptor antagonist L732138 and the AKT inhibitor LY294002. The results indicate that substance P reduced the ischemia-related release of lactate dehydrogenase in both preparations and the degree of apoptosis and necrosis in the hypoxic left ventricular slices, indicating its ability to attenuate cell damage; and induced AKT phosphorylation, with both the AKT inhibitor and NK-1 receptor antagonist preventing the increased phosphorylation of AKT and the ability of substance P to attenuate hypoxic cellular damage. It is concluded that substance P reduces ischemia/hypoxia-induced myocardial cell death by acting directly on cardiac cells to initiate cell survival pathways via the NK-1 receptor and AKT.

Heat shock protein 90/Akt pathway participates in the cardioprotective effect of exogenous hydrogen sulfide against high glucose-induced injury to H9c2 cells

“…Chanoit et al reported that Akt mediated exogenous zinc-induced cardioprotection against reperfusion injury (45). The Akt pathway is also involved in the cardioprotection of substance P against ischemic/hypoxia-induced myocardial cell death (46). Moreover, the impaired activation of Akt has been shown to participate in diabetic cardiomyopathy (34,35).…”

Substance P Receptor in the Rat Heart and Regulation of Its Expression in Long-Term Diabetes

“…However, isolated neonatal rat cardiomyocytes have been shown to possess NK1R and NK3R mRNAs, but not NK2R mRNA ( Church et al, 1996 ). Recently, the presence of NK1R on isolated adult cardiomyocytes has been shown in rat ( Jubair et al, 2015 ). Although our results and the results of other authors did not confirm the presence of NK1R in cardiomyocytes, data obtained by functional studies suggest a direct protective action of SP on cardiomyocytes by NK1R ( Jubair et al, 2015 ).…”

“…However, accumulating evidence indicates that SP is cardioprotective due to its potent coronary vasodilator effects ( Chiao and Caldwell, 1995 ; Ustinova et al, 1995 ; Wang et al, 2011 ). Moreover, a recent study suggests that cardioprotective role of SP performed throughout its direct actions on cardiomyocytes ( Jubair et al, 2015 ). Therefore, the purpose of this study was to investigate the gene and protein expression of NK1R in all heart compartments of rats.…”

Substance P Inhibits the Collagen Synthesis of Rat Myocardial Fibroblasts Induced by Ang II

“…This further indicates that Ang II might activate the aforementioned downstream signaling pathway genes by acting on TGF-β1 and thereby promoting the activation of the genes related to collagen synthesis in CFBs. Other studies showed that the protective effect of the combined SP and NK1 receptors on injured myocardial cells in myocardial ischemia might be realized by AKT signaling pathways [27]. Therefore, SP can be an advantageous protection factor in myocardial fibrosis and play its role by way of downstream pathways when bound with SP receptors.…”