Abstract
Background and Objective: Sphingosine 1-phosphate (S1P), and S1P receptor modulator fingolimod have been suggested to play important cardioprotective role in animal models of myocardial ischemia/reperfusion injuries. To understand the cardioprotective function of S1P and its mechanism in vivo, we analyzed apoptotic, inflammatory biomarkers, and myocardial fibrosis in an in vivo heterotopic rat heart transplantation model.Methods: Heterotopic heart transplantation is performed in 60 Sprague–Dawley (SD) rats (350–400 g). The heart transplant recipients (n = 60) are categorized into Group A (control) and Group B (fingolimod treated 1 mg/kg intravenous). At baseline with 24 h after heart transplantation, blood and myocardial tissue are collected for analysis of myocardial biomarkers, apoptosis, inflammatory markers, oxidative stress, and phosphorylation of Akt/Erk/STAT-3 signaling pathways. Myocardial fibrosis was investigated using Masson’s trichrome staining and L-hydroxyline.Results: Fingolimod treatment activates both Reperfusion Injury Salvage Kinase (RISK) and Survivor Activating Factor Enhancement (SAFE) pathways as evident from activation of anti-apoptotic and anti-inflammatory pathways. Fingolimod treatment caused a reduction in myocardial oxidative stress and hence cardiomyocyte apoptosis resulting in a decrease in myocardial reperfusion injury. Moreover, a significant (p < 0.001) reduction in collagen staining and hydroxyproline content was observed in fingolimod treated animals 30 days after transplantation demonstrating a reduction in cardiac fibrosis.Conclusion: S1P receptor activation with fingolimod activates anti-apoptotic and anti-inflammatory pathways, leading to improved myocardial salvage causing a reduction in cardiac fibrosis.
Highlights
Heart transplantation is the ultimate treatment option for heart failure (HF) (Koerner et al, 2000), which is a major health problem worldwide, with a prevalence of 23 million worldwide and 5.8 million in the United States alone (Benjamin et al, 2017)
Fingolimod treatment caused a reduction in myocardial oxidative stress and cardiomyocyte apoptosis resulting in a decrease in myocardial reperfusion injury
Sphingosine 1-phosphate (S1P) receptor activation with fingolimod activates anti-apoptotic and antiinflammatory pathways, leading to improved myocardial salvage causing a reduction in cardiac fibrosis
Summary
Heart transplantation is the ultimate treatment option for heart failure (HF) (Koerner et al, 2000), which is a major health problem worldwide, with a prevalence of 23 million worldwide and 5.8 million in the United States alone (Benjamin et al, 2017). Cardiac fibrosis is one of the main factors in the development and progression of HF. Targeting the development and progression of cardiac fibrosis is a critical goal in the treatment of HF (Miner and Miller, 2006; Opie et al, 2006). Most common cause of cardiac dysfunction and mortality in cardiac transplant patients is due to I/R injury (Murata et al, 2004; Tanaka et al, 2005). Low potassium solutions give some positive evidence for better cardiac graft preservation and demonstrate attenuation of grafted heart damage related to cold storage and I/R injury (Rudd and Dobson, 2009). To understand the cardioprotective function of S1P and its mechanism in vivo, we analyzed apoptotic, inflammatory biomarkers, and myocardial fibrosis in an in vivo heterotopic rat heart transplantation model
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