Canonical transient receptor potential channel 1 aggravates myocardial ischemia-and-reperfusion injury by upregulating reactive oxygen species
10.1016/j.jpha.2023.08.018
- Author:
Hui-Nan ZHANG
1
;
Meng ZHANG
;
Wen TIAN
;
Wei QUAN
;
Fan SONG
;
Shao-Yuan LIU
;
Xiao-Xiao LIU
;
Dan MO
;
Yang SUN
;
Yuan-Yuan GAO
;
Wen YE
;
Ying-Da FENG
;
Chang-Yang XING
;
Chen YE
;
Lei ZHOU
;
Jing-Ru MENG
;
Wei CAO
;
Xiao-Qiang LI
Author Information
1. Department of Health Management,Second Affiliated Hospital,Fourth Military Medical University,Xi'an,710038,China;Department of Pharmacology,School of Pharmacy,Fourth Military Medical University,Xi'an,710032,China;Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine,School of Pharmacy,Fourth Military Medical University
- Keywords:
TRPC1;
Myocardial ischemia/reperfusion;
Reactive oxygen species;
OGDHL
- From:
Journal of Pharmaceutical Analysis
2023;13(11):1309-1325
- CountryChina
- Language:Chinese
-
Abstract:
The canonical transient receptor potential channel(TRPC)proteins form Ca2+-permeable cation channels that are involved in various heart diseases.However,the roles of specific TRPC proteins in myocardial ischemia/reperfusion(I/R)injury remain poorly understood.We observed that TRPC1 and TRPC6 were highly expressed in the area at risk(AAR)in a coronary artery ligation induced I/R model.Trpc1-/-mice exhibited improved cardiac function,lower serum Troponin T and serum creatine kinase level,smaller infarct volume,less fibrotic scars,and fewer apoptotic cells after myocardial-I/R than wild-type or Trpc6-/-mice.Cardiomyocyte-specific knockdown of Trpc1 using adeno-associated virus 9 mitigated myocardial I/R injury.Furthermore,Trpc1 deficiency protected adult mouse ventricular myocytes(AMVMs)and HL-1 cells from death during hypoxia/reoxygenation(H/R)injury.RNA-sequencing-based transcriptome analysis revealed differential expression of genes related to reactive oxygen species(ROS)generation in Trpc1-/-cardiomyocytes.Among these genes,oxoglutarate dehydrogenase-like(Ogdhl)was markedly downregulated.Moreover,Trpc1 deficiency impaired the calcineurin(CaN)/nuclear factor-kappa B(NF-κB)signaling pathway in AMVMs.Suppression of this pathway inhibited Ogdhl upregulation and ROS generation in HL-1 cells under H/R conditions.Chromatin immunoprecipitation assays confirmed NF-κB binding to the Ogdhl promoter.The cardioprotective effect of Trpc1 deficiency was canceled out by overexpression of NF-κB and Ogdhl in cardiomyocytes.In conclusion,our findings reveal that TRPC1 is upregulated in the AAR following myocardial I/R,leading to increased Ca2+influx into associated cardiomyocytes.Subsequently,this upregulates Ogdhl expression through the CaN/NF-κB signaling pathway,ultimately exacerbating ROS production and aggravating myocardial I/R injury.
