Tabersonine attenuates Angiotensin II-induced cardiac remodeling and dysfunction through targeting TAK1 and inhibiting TAK1-mediated cardiac inflammation.

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.

• Authors: Chengyi Dai, Wu Luo, Yanghao Chen, Siyuan Shen, Zhe Wang, Ruijie Chen, Jun Wang, Nipon Chattipakorn, Weijian Huang, Guang Liang
• Journal: Phytomedicine : international journal of phytotherapy and phytopharmacology (Phytomedicine) Vol. 103 Pg. 154238 (Aug 2022) ISSN: 1618-095X [Electronic] Germany
• PMID: 35696800 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier GmbH. All rights reserved.

Chemical References

• Indole Alkaloids
• Quinolines
• Angiotensin II
• tabersonine
• MAP Kinase Kinase Kinases
• MAP kinase kinase kinase 7

Topics

• Angiotensin II (pharmacology)
• Animals
• Cardiomegaly (chemically induced)
• Fibrosis
• Heart Failure (drug therapy, pathology)
• Indole Alkaloids (pharmacology)
• Inflammation (drug therapy, pathology)
• MAP Kinase Kinase Kinases (metabolism)
• Mice
• Mice, Inbred C57BL
• Myocytes, Cardiac
• Quinolines
• Rats
• Signal Transduction
• Ventricular Remodeling