Melatonin fine-tunes intracellular calcium signals and eliminates myocardial damage through the IP3R/MCU pathways in cardiorenal syndrome type 3

Jin Wang, Sam Toan, Ruibing Li, Hao Zhou

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Cardiorenal syndrome type-3 (CRS-3) is characterized by acute cardiac injury induced by acute kidney injury. Here, we investigated the causes of CRS-3 by analyzing cardiac function after renal ischemia–reperfusion injury (IRI) using echocardiography and evaluation of pro-inflammatory markers, calcium balance, mitochondrial function, and cardiomyocyte death. Our results show that renal IRI reduces cardiac diastolic function associated with cardiomyocyte death and inflammatory responses. Renal IRI also disrupts cardiomyocyte energy metabolism, induces calcium overload, and impairs mitochondrial function, as evidenced by reduced mitochondrial membrane potential and increased mitochondrial fission. Further, renal IRI induces phosphorylation of inositol 1,4,5-trisphosphate receptor (IP3R) and expression of mitochondrial calcium uniporter (MCU), resulting in cytoplasmic calcium overload and mitochondrial calcium accumulation. Pretreatment with melatonin attenuates renal IRI-mediated cardiac damage by maintaining myocardial diastolic function and reducing cardiomyocyte death. Melatonin also inhibits IP3R phosphorylation and MCU expression, thereby alleviating cytoplasmic and mitochondrial calcium overload. Blockade of IP3R has similar cardioprotective effects, whereas MCU activation abrogates the melatonin-mediated cardioprotection. These results show that the negative effects of renal IRI on myocardial viability and cardiac function are caused by induced IP3R phosphorylation, MCU upregulation, and calcium overload. Melatonin protects cardiac function against CRS-3 by suppressing IP3R-MCU signaling.

Original languageEnglish (US)
Article number113832
JournalBiochemical Pharmacology
Volume174
DOIs
StatePublished - Apr 2020
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported in part by China Postdoctoral Science Foundation ( 2019TQ0128 ) and the NSFC ( 81900252 , 81770261 , 81900254 and 91749128 ).

Publisher Copyright:
© 2020 Elsevier Inc.

Keywords

  • CRS-3
  • Calcium overload
  • IP3R
  • MCU
  • Melatonin
  • Mitochondria

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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