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  • Propranolol initially discovered in is first and most widely

    2019-08-21

    Propranolol, initially discovered in 1964, is first and most widely studied as a non-selective beta-blocker. Propranolol through β-adrenergic receptor blockade has reduced heart rate and blood pressure and have anti-arrhythmogenic and anti-ischemic effects, and been proposed as an effective strategy for many CVDs, such as hypertension, cardiac arrhythmias, and leptomycin b pectoris (Al-Majed et al., 2017). It is therefore not surprising here to observe that the administration of propranolol resulted in the relatively low level of the heart mass, index interventricular septum and left ventricular posterior wall in mice stimulated by isoprenaline, and rescued cardiac function, which coincides with many previous studies (Marano et al., 2002, Pantos et al., 2000). At the same time, we found for the first time that the treatment with propranolol could prevent the decrease of the expression of ClC-3 in the heart of mice induced by isoprenaline, suggested that ClC-3 maybe play a role in cardiac hypertrophy stimulated by the activation of β-adrenergic receptor. Nevertheless, a propranolol dosage of 10mg/kg/day for experiments in vivo may not completely block the β-adrenergic receptor. Our results show that treatment of isoprenaline combined with propranolol almost fully transform these negative effect induced by isoprenaline alone. Another possible mechanism can interpret this phenomenon. In addition to mainly block the β-adrenergic receptor propranolol may also directly up-regulate C1C-3 expression or activate ClC-3 chloride channel. To confirm the protective effects of ClC-3 on myocardiac hypertrophy induced by isoprenaline, we pretreated isoprenaline-stimulated mice with adeno-associated virus (AAV9) carrying ClC-3. Adeno-associated virus (AAV) is a small naked, single stranded virus first discovered in 1965(Atchison et al., 1965). Up to now, more than 12 different serotypes and hundreds of capsid variants have been found (Duan, 2016). Due to its safety and the ability to elicit robust and long-term transgene expression in animals and humans, AAV has garnered the growing interest and become the most preferred vector for gene therapy over last two decades (Clement and Grieger, 2016, Duan, 2016). AAV9 mediated gene therapy was thought as a good candidate for cardiomyopathy (Duan, 2016). In our current study, pretreatment of AAV9-mediated ClC-3 expression in myocardium in isoprenaline-induced hypertrophic mice showed minor heart mass indexes, thinner interventricular septums and left ventricular walls, lower the mRNA expression of ANF and β-MHC than that of AAV9-vector control, and displayed the protective effect on myocardiac hypertrophy. Atrial natriuretic factor (ANF) and β-myosin heavy chain (β-MHC), as familiar molecular markers of hypertrophy, are produced and released by cardiac myocytes as a compensatory mechanism to positively modulate the cardiac functions against cardiac hypertrophy (Hong et al., 2017). Many studies have demonstrated that ligands of adrenergic receptors such as isoprenaline used in our present investigation could stimulate ANF and β-MHC expression with the increased CVD risk (Palazzesi et al., 2006, Saadane et al., 1999), but it\'s not well known about the underlying mechanisms. Several studies found that ANF and β-MHC expression levels were influenced by the elevation of cytosolic calcium and the activation of PKC, ERKs, p38 MAP kinase, NF-kappa-B, PI3K/AKT or JNKs (Hong et al., 2017, Sergeeva and Christoffels, 2013, Sun et al., 2016). Li et al. found that miR-145 down-regulated ANF and β-MHC expression and displayed the protection against cardiomyocyte hypertrophy induced by isoprenaline through targeting the expression and localization of GATA6 (Li et al., 2013). In the present study, we found that isoprenaline stimulated ANF and β-MHC mRNA expression accompanied by the reduction of ClC-3 expression in primary rat neonatal cardiomyocytes and C57/BL/6 mice, and that could be inhibited by propranolol in C57/BL/6 mice. Interestingly, pretreatment of AAV9-mediated ClC-3 expression in myocardium could down-regulate ANF and β-MHC mRNA expression and rescue the in cardiac hypertrophy induced by isoprenaline.