Trans-cinnamaldehyde suppresses microtubule detyrosination and alleviates cardiac hypertrophy

Eur J Pharmacol. 2022 Jan 5:914:174687. doi: 10.1016/j.ejphar.2021.174687. Epub 2021 Dec 6.

Abstract

Background: Trans-cinnamaldehyde (TCA) is a main compound of Cinnamomum cassia, used in traditional Chinese medicine to treat many ailments. Increasing evidence has demonstrated the therapeutic effects of TCA in cardiovascular diseases.

Purpose: The present study aimed to determine whether TCA exerts antihypertrophic effects in vitro and in vivo and to elucidate the underlying mechanisms of these effects.

Methods: Neonatal rat cardiac myocytes (NRCMs) and adult mouse cardiac myocytes (AMCMs) were treated with 50 μΜ phenylephrine (PE) for 48 h. Tubulin detyrosination, store-operated Ca2+ entry (SOCE), stromal interaction molecule-1 (STIM1)/Orai1 translocation, and calcineurin/nuclear factor of activated T-cells (NFAT) signaling pathways were analyzed in NRCMs. Meanwhile, tubulin detyrosination, junctophilin-2, T-tubule distribution pattern, Ca2+ handling, and sarcomere shortening were observed in AMCMs. Male C57BL/6 mice were stimulated with PE (70 mg/kg per day) with or without TCA treatment for 2 weeks. Cardiac hypertrophy and tubulin detyrosination were also assessed.

Results: TCA was confirmed to alleviate cardiac hypertrophy induced by PE stimulation in vitro and in vivo. PE-induced cardiac hypertrophy was associated with excessive tubulin detyrosination and overexpression of vasohibin 1 (VASH1) and small vasohibin binding protein (SVBP), two key proteins responsible for tubulin detyrosination. These effects were largely blocked by TCA administration. PE treatment also enhanced SOCE with massive translocation of STIM1 and Orai1, Ca2+ mishandling, reduced sarcomere shortening, junctophilin-2, and T-tubule redistribution, all of which were significantly ameliorated by TCA administration.

Conclusion: Our study indicated that the therapeutic effects of TCA against cardiac hypertrophy may be associated with its ability to reduce tubulin detyrosination.

Keywords: Cardiac hypertrophy; Junctophilin-2; Microtubule; SOCE; Trans-cinnamaldehyde; Tubulin detyrosination.

MeSH terms

  • Acrolein / analogs & derivatives*
  • Acrolein / pharmacology
  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Cardiomegaly* / drug therapy
  • Cardiomegaly* / metabolism
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins / metabolism
  • Membrane Proteins / metabolism
  • Mice
  • Microtubules* / drug effects
  • Microtubules* / metabolism
  • Myocytes, Cardiac* / drug effects
  • Myocytes, Cardiac* / metabolism
  • Myocytes, Cardiac* / ultrastructure
  • Rats
  • Signal Transduction / drug effects
  • Treatment Outcome
  • Tubulin / metabolism*
  • Tubulin Modulators / pharmacology

Substances

  • Antineoplastic Agents, Phytogenic
  • Carrier Proteins
  • Cell Cycle Proteins
  • Membrane Proteins
  • Tubulin
  • Tubulin Modulators
  • VASH1 protein, rat
  • Vash1 protein, mouse
  • junctophilin
  • Acrolein
  • cinnamaldehyde