Tabersonine attenuates Angiotensin II-induced cardiac remodeling and dysfunction through targeting TAK1 and inhibiting TAK1-mediated cardiac inflammation.
Phytomedicine
; 103: 154238, 2022 Aug.
Article
em En
| MEDLINE
| ID: mdl-35696800
ABSTRACT
BACKGROUND:
Angiotensin II (Ang II)-induced cardiac inflammation contribute to pathological cardiac remodeling and hypertensive heart failure (HF). Tabersonine (Tab) is an indole alkaloid mainly isolated from Catharanthus roseus and exhibits anti-inflammatory activity in various systems. However, the role of Tab in hypertensive HF and its molecular targets remains unknown. HYPOTHESIS/PURPOSE:
We aimed to investigate potential cardioprotective effects and mechanism of Tab against Ang II-induced cardiac injuries.METHODS:
C57BL/6 mice were administered Ang II (at 1000 ng/kg/min) by micro-osmotic pump infusion for 30 days to develop hypertensive HF. Tab at 20 and 40 mg/kg/day was administered during the last 2 weeks to elucidate the cardioprotective properties. Cultured cardiomyocyte-like H9c2 cells and rat primary cardiomyocytes were used for mechanistic studies of Tab.RESULTS:
We demonstrate for the first time that Tab provides protection against Ang II-induced cardiac dysfunction in mice, associated with reduced cardiac inflammation and fibrosis. Mechanistically, we show that Tab may interacts with TAK1 to inhibit Ang II-induced TAK1 ubiquitination and phosphorylation. Disruption of TAK1 activation by Tab blocked downstream NF-κB and JNK/P38 MAPK signaling activation and decreased cardiac inflammation and fibrosis both in vitro and in vivo. TAK1 knockdown also blocked Ang II-induced cardiomyocytes injuries and prevented the innately pharmacological effects of Tab.CONCLUSION:
Our results indicate that Tab protects hearts against Ang II-mediated injuries through targeting TAK1 and inhibiting TAK1-mediated inflammatory cascade and response. Thus, Tab may be a potential therapeutic candidate for hypertensive HF.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Angiotensina II
/
MAP Quinase Quinase Quinases
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Insuficiência Cardíaca
Limite:
Animals
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article