Melatonin-Induced Protective Effects on Cardiomyocytes Against Reperfusion Injury Partly Through Modulation of IP3R and SERCA2a Via Activation of ERK1

Abstract

BackgroundMelatonin is a neuroendocrine hormone synthesized primarily by the pineal gland that is indicated to effectively prevent myocardial reperfusion injury. It is unclear whether melatonin protects cardiac function from reperfusion injury by modulating intracellular calcium homeostasis.ObjectiveDemonstrate that melatonin protect against myocardial reperfusion injury through modulating IP3R and SERCA2a to maintain calcium homeostasis via activation of ERK1 in cardiomyocytes.MethodsIn vitro experiments were performed using H9C2 cells undergoing simulative hypoxia/reoxygenation (H/R) induction. Expression level of ERK1, IP3R and SERCA2a were assessed by Western Blots. Cardiomyocytes apoptosis was detected by TUNEL. Phalloidin-staining was used to assess alteration of actin filament organization of cardiomyocytes. Fura-2 /AM was used to measure intracellular Ca2+ concentration. Performing in vivo experiments, myocardial expression of IP3R and SERCA2a were detected by immunofluorescence staining using myocardial ischemia/ reperfusion (I/R) model in rats.ResultsIn vitro results showed that melatonin induces ERK1 activation in cardiomyocytes against H/R which was inhibited by PD98059 (ERK1 inhibitor). The results showed melatonin inhibit apoptosis of cardiomyocytes and improve actin filament organization in cardiomyocytes against H/R, because both could be reversed by PD98059. Melatonin was showed to reduce calcium overload, further to inhibit IP3R expression and promote SERCA2a expression via ERK1 pathway in cardiomyocytes against H/R. Melatonin induced lower IP3R and higher SERCA2a expression in myocardium that were reversed by PD98059.Conclusionmelatonin-induced cardioprotection against reperfusion injury is at least partly through modulation of IP3R and SERCA2a to maintain intracellular calcium homeostasis via activation of ERK1.

Melatonin’s Impact on Antioxidative and Anti-Inflammatory Reprogramming in Homeostasis and Disease

“…As previously discussed, the most prominent protective mechanism lies in its antioxidant potential [ 19 , 116 ]. In the field of cardiovascular effects, melatonin protects against ischemia/reperfusion injury (IRI) [ 62 , 117 , 118 , 119 , 120 , 121 ] and hypertension [ 122 , 123 , 124 ], as an endogenous effect, nutritional supplement, or acute parenteral administration [ 125 , 126 ]. In addition, it appears that other promising effects such as anti-apoptotic, anti-inflammatory [ 127 ], preconditioning [ 118 , 128 ], myocardial infarction [ 129 , 130 , 131 ], and even an implication in heart failure [ 132 , 133 , 134 , 135 ] have been documented.…”

“…Melatonin has demonstrated its potential role in protecting the myocardium against ischemia/reperfusion injury in multiple settings [ 62 , 117 , 120 , 121 , 128 ]. At low concentrations (4 mg/kg/day), it activates several signaling pathways that offer protection against IRI [ 20 , 174 ].…”

Role of the Extracellular Signal-Regulated Kinase 1/2 Signaling Pathway in Ischemia-Reperfusion Injury

“…The mechanism underlying IRI is very complicated and involves primary injury in the early stage of ischemia and secondary injury after reperfusion. Tissue damage due to IRI not only depends on the degree of blood flow reduction, but is also related to intracellular calcium overload (Hu et al, 2018), oxidative stress, the inflammatory response (Al-Salam and Hashmi, 2018), neurotoxicity of excitatory amino acids (Dohmen et al, 2005), excessive nitric oxide synthesis, energy metabolism disorders, and other factors. Many factors that induce IRI influence each other, leading to neurotoxicity and eventually local brain tissue damage and necrosis/apoptosis of nerve cells.…”

Reperfusion Arrhythmias Increase after Superior Cervical Ganglionectomy Due to Conduction Disorders and Changes in Repolarization

“…Triggered activity is strongly related to calcium overload, and it can be attributed to reduced levels of SERCA 2A in our experimental model [33,44]. SERCA 2A is the main ATPase responsible for calcium reuptake at the sarcoplasmic reticulum [45,46].…”