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
,
2
,
3
;
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
2. Department of Pharmacology,School of Pharmacy,Fourth Military Medical University,Xi'an,710032,China
3. 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.
