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5-HT2B receptor blockade attenuates β-adrenergic receptor-stimulated myocardial remodeling in rats via inhibiting apoptosis: role of MAPKs and HSPs

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Abstract

Recent studies have proposed the potential role of 5-HT2B receptor (5-HT2BR) blockade in alleviating myocardial dysfunction; hitherto, the regulatory pathway for its protective effect has remained enigmatic. In the present study, we sought to investigate the role of SB-204741, a 5-HT2BR blocker in isoproterenol-induced myocardial remodeling in rats and its cross-talk with apoptosis and mitogen activated protein kinase (MAPKs)/heat shock proteins (HSPs) pathway. To assess this hypothesis, we measured the effect of SB-204741 (0.25–1.0 mg/kg/day, i.p.) in isoproterenol (85 mg/kg/day, s.c.)-induced myocardial remodeling in rats. SB-204741 dose dependently improved hemodynamic and ventricular functions following isoproterenol-induced myocardial injury. This amelioration was well substantiated with reduced expression of 5-HT2B, inflammatory proteins (NF-κBp65, IKK-β, TNF-α, IL-6, and Cox-2), MAPKs (p-p38/p38 and p-JNK/JNK ratio) accompanied with increased protein expression of HSPs (αB-crystallin, Hsp27 and Hsp70), autophagy (LC3 and Beclin-1) and p-ERK/ERK ratio. Additionally, SB-204741 inhibited apoptotic signaling pathway as there was decreased DAPI/TUNEL positivity and protein expression of cytochrome c, Bax, and caspase-3 along with increased Bcl-2 expression. Preservation of histopathological and ultrastructural components, normalization of nitric oxide level, endogenous antioxidants and myocyte injury marker enzymes were also observed. In conclusion, inhibition of apoptosis via modulation of MAPKs/HSPs is essential for 5-HT2BR blockade mediated cardioprotective effect.

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Acknowledgments

The authors gratefully acknowledge Mr. Deepak and Mr. BM Sharma for their technical assistance during the course of the surgery and in the preparation of histopathological slides and the Department of Science and Technology, Govt. of India for providing fellowship to Saurabh Bharti (IF10332) and Neha Rani (IF120584) under the INSPIRE-DST-Fellowship programme.

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None declared.

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Authors and Affiliations

  1. Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, 110029, India

    Saurabh Bharti, Neha Rani, Jagriti Bhatia & Dharamvir Singh Arya

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  1. Saurabh Bharti
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  2. Neha Rani
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  3. Jagriti Bhatia
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Correspondence to Dharamvir Singh Arya.

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Bharti, S., Rani, N., Bhatia, J. et al. 5-HT2B receptor blockade attenuates β-adrenergic receptor-stimulated myocardial remodeling in rats via inhibiting apoptosis: role of MAPKs and HSPs. Apoptosis 20, 455–465 (2015). https://doi.org/10.1007/s10495-014-1083-z

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