TRPA1 deficiency attenuates cardiac fibrosis via regulating GRK5/NFAT signaling in diabetic rats.

Abstract

BACKGROUND:

Transient receptor potential ankyrin 1 (TRPA1) has been linked to the development of various cardiovascular diseases, but its role in diabetic cardiomyopathy is not well understood. This study aimed to investigate the protective effects of TRPA1 deficiency on diabetic cardiomyopathy in rats with streptozotocin-induced diabetes and in neonatal rat cardiac fibroblasts (CFs) exposed to high glucose (HG).

METHODS:

Cardiac TRPA1 expression levels were measured in diabetic rats. Cardiac function, remodeling, and fibrosis were analyzed in Sprague-Dawley (SD) rats and TRPA1-deficient rats with diabetic cardiomyopathy. In vitro, fibrosis was measured in CFs exposed to HG. Additionally, 1,8-cineole, a natural inhibitor of TRPA1, was used to treat SD rats with diabetic cardiomyopathy.

RESULTS:

TRPA1 expression was increased in the heart tissue of diabetic rats and in CFs treated with HG. TRPA1 deficiency significantly improved cardiac function in diabetic rats, as evidenced by improved echocardiography and reduced cardiac hypertrophy and fibrosis. In vitro, TRPA1 deficiency suppressed the transformation of HG-induced CFs into myofibroblasts. The cardioprotective effect of TRPA1 deficiency was found to inhibit cardiac fibrosis by regulating GRK5/NFAT signaling. Furthermore, inhibition of GRK5/NFAT signaling abolished the promotion of CF transformation into myofibroblasts by TRPA1 activation. Inhibition of TRPA1 activation by 1,8-cineole reduced cardiac dysfunction and remodeling in diabetic rats by regulating GRK5/NFAT signaling.

CONCLUSIONS:

TRPA1 deficiency reduced cardiac fibrosis in diabetic rats and inhibited HG-induced CF activation in vitro by regulating GRK5/NFAT signaling. The TRPA1 inhibitor 1,8-cineole may serve as a novel therapeutic agent for the treatment of diabetic cardiomyopathy.

• Authors: Menglong Wang, Mengmeng Zhao, Shuwan Xu, Zihui Zheng, Jishou Zhang, Wei Pan, Zheng Yin, Jianfang Liu, Cheng Wei, Jun Wan, Yao Xu
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 214 Pg. 115671 (08 2023) ISSN: 1873-2968 [Electronic] England
• PMID: 37380112 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Elsevier Inc. All rights reserved.

Chemical References

• Eucalyptol

Topics

• Rats
• Animals
• Diabetic Cardiomyopathies (drug therapy, metabolism)
• Diabetes Mellitus, Experimental (complications, drug therapy, chemically induced)
• Rats, Sprague-Dawley
• Eucalyptol (therapeutic use)
• Fibrosis