Abstract
Disruption of Th17/Tregs homeostasis plays a crucial role in governing the immune response during myocardial fibrosis and its progression to heart failure. The present study aimed to assess for the first time the possible protection afforded by rupatadine against isoproterenol-induced heart failure in rats. It also explored the role of PI3k/Akt as a possible mechanistic pathway, through which rupatadine could modulate Th17/Tregs balance to display its effect. Isoproterenol (85 and 170 mg/kg/day) was injected subcutaneously for 2 successive days, respectively and rupatadine (4 mg/kg/day) was then given orally for 14 days with or without wortmannin (PI3K/Akt inhibitor). Rupatadine succeeded to completely ameliorate isoproterenol-induced cardiac dysfunction as demonstrated by improvements of electrocardiographic and echocardiographic measurements. Moreover, rupatadine prevented the marked elevation of PAF and oxidative stress in addition to Th17 promoting cytokines (IL-6, IL-23, and TGF-β). Accordingly, rupatadine prevented Th17 stimulation or expansion as indicated by increased Foxp3/RORγt ratio and decreased production of its pro-inflammatory cytokine (IL-17). Rupatadine treatment mitigated isoproterenol-induced activation of STAT-3 signaling and the imbalance in p-Akt/total Akt ratio affording marked decrease in atrogin-1 and apoptotic biomarkers. Finally, this therapy was effective in averting cardiac troponin loss and reverting the histological alterations as assessed by myocardial fibrosis and hypertrophy grading. Contrariwise, co-administration of wortmannin mostly attenuated the protective effects of rupatadine affording more or less similar results to that of isoproterenol-untreated rats. In conclusion, rupatadine could be an effective therapy against the development of isoproterenol-induced heart failure where PI3K/Akt pathway seems to play a crucial role in its protective effect.
Highlights
Heart failure (HF) is a common pathophysiologic event following many cardiovascular disease conditions including cardiac surgery as well as myocardial ischemia, myocardial infarction (MI) and hypertrophy (Wang et al, 2017)
Treatment with RUP completely reverted changes in Heart Weight Index (HWI), an effect that was abolished by co-administration of wortmannin, a selective inhibitor of PI3K/Akt pathway (Table 1)
ISO administration induced conduction and contraction abnormalities as indicated by significant increase in QT interval, QRS duration, left ventricular enddiastolic diameter (LVEDD), and left ventricular end-systolic diameter (LVESD) measurements together with a significant decrease in heart rate (HR) and EF%. These results were associated with a marked rise in serum level of Brain natriuretic peptide (BNP) confirming the presence of cardiac dysfunction and HF
Summary
Heart failure (HF) is a common pathophysiologic event following many cardiovascular disease conditions including cardiac surgery as well as myocardial ischemia, myocardial infarction (MI) and hypertrophy (Wang et al, 2017). These events usually begin with myocardial damage and fibrosis which increase the stiffness of heart muscle and cause subsequent mechanical and electrical dysfunction leading to arrhythmia, HF, and even sudden death (Brilla et al, 1991). Upon cardiac injury, sustained inflammatory response plays a key role in the process of cardiac fibrosis and remodeling with progression to left ventricular hypertrophy and HF (Diwan et al, 2005). PAF acts via a G-protein-coupled receptor (PAFR), upregulating the secretion of a variety of cytokines and promoting neutrophils chemotaxis through platelet-leukocytes conjugation (Sugano et al, 2001)
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