Cinnamic acid mitigates left ventricular hypertrophy and heart failure in part through modulating FTO-dependent N6-methyladenosine RNA modification in cardiomyocytes

Yimeng Cui; Peiwei Wang; Mengli Li; Yujue Wang; Xinmiao Tang; Jingang Cui; Yu Chen; Teng Zhang

doi:10.1016/j.biopha.2023.115168

Cinnamic acid mitigates left ventricular hypertrophy and heart failure in part through modulating FTO-dependent N⁶-methyladenosine RNA modification in cardiomyocytes

Biomed Pharmacother. 2023 Sep:165:115168. doi: 10.1016/j.biopha.2023.115168. Epub 2023 Jul 13.

Authors

Yimeng Cui¹, Peiwei Wang², Mengli Li¹, Yujue Wang¹, Xinmiao Tang¹, Jingang Cui², Yu Chen³, Teng Zhang⁴

Affiliations

¹ Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
² Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China; Clinical Research Institute of Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai 200437, China.
³ Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China; Clinical Research Institute of Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai 200437, China; Laboratory of Clinical and Molecular Pharmacology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China. Electronic address: chenyu@shutcm.edu.cn.
⁴ Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China; Clinical Research Institute of Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai 200437, China. Electronic address: zhangteng2089@shutcm.edu.cn.

PMID: 37453198
DOI: 10.1016/j.biopha.2023.115168

Abstract

Left ventricular hypertrophy leads to heart failure, a serious medical condition associated with high rates of hospitalization and mortality. Limited success with the existing pharmacological treatments necessitates the development of mechanisms-based new therapies to better control the progression from left ventricular hypertrophy to heart failure. The current work investigated the pharmacological potentials and mechanisms of naturally occurring cinnamic acid in the treatment of left ventricular hypertrophy and heart failure. The in vitro findings reveal that cinnamic acid attenuates the hypertrophic responses and mitochondrial dysfunction in the phenylephrine (PE)-stimulated cardiomyocytes. Furthermore, cinnamic acid offsets PE-induced increases in N⁶-methyladenosine (m⁶A) RNA modification and reductions in the expression of the key m⁶A demethylase FTO in cardiomyocytes. Most importantly, FTO knockdown abrogates anti-hypertrophic and mitochondrial protective effects of cinnamic acid in the PE-stimulated cardiomyocytes. The in vivo results further demonstrate that cinnamic acid mitigates left ventricular hypertrophy, left ventricular systolic dysfunction and ultrastructural impairment of cardiomyocyte mitochondria and myofibrils in the mice subjected to transverse aortic constriction (TAC)-induced pressure overload. Moreover, FTO knockdown abolishes these beneficial effects of cinnamic acid in the TAC mice. In conclusion, the work here demonstrates for the first time that cinnamic acid is effective at mitigating pressure overload-induced left ventricular hypertrophy and heart failure in part by modulating the expression of FTO and the level of FTO-dependent m⁶A RNA modification in cardiomyocytes. These novel findings warrant further evaluation of cinnamic acid as a pharmacological agent/component to complement the existing treatment of pressure overload-mediated left ventricular hypertrophy and heart failure.

Keywords: Cinnamic acid; FTO; Heart failure; Left ventricular hypertrophy; Mitochondria; N(6)-methyladenosine RNA modification.

MeSH terms

Alpha-Ketoglutarate-Dependent Dioxygenase FTO
Animals
Disease Models, Animal
Heart Failure*
Hypertrophy, Left Ventricular*
Mice
Mice, Inbred C57BL
Myocytes, Cardiac
Phenylephrine / pharmacology
RNA / metabolism

Substances

cinnamic acid
N-methyladenosine
Phenylephrine
RNA
FTO protein, mouse
Alpha-Ketoglutarate-Dependent Dioxygenase FTO