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TRPC channels blockade abolishes endotoxemic cardiac dysfunction by hampering intracellular inflammation and Ca2+ leakage.
- Source :
- Nature Communications; 12/2/2022, Vol. 13 Issue 1, p1-21, 21p
- Publication Year :
- 2022
-
Abstract
- Intracellular Ca<superscript>2+</superscript> dysregulation is a key marker in septic cardiac dysfunction; however, regulation of the classic Ca<superscript>2+</superscript> regulatory modules cannot successfully abolish this symptom. Here we show that the knockout of transient receptor potential canonical (TRPC) channel isoforms TRPC1 and TRPC6 can ameliorate LPS-challenged heart failure and prolong survival in mice. The LPS-triggered Ca<superscript>2+</superscript> release from the endoplasmic reticulum both in cardiomyocytes and macrophages is significantly inhibited by Trpc1 or Trpc6 knockout. Meanwhile, TRPC's molecular partner — calmodulin — is uncoupled during Trpc1 or Trpc6 deficiency and binds to TLR4's Pococurante site and atypical isoleucine-glutamine-like motif to block the inflammation cascade. Blocking the C-terminal CaM/IP3R binding domain in TRPC with chemical inhibitor could obstruct the Ca<superscript>2+</superscript> leak and TLR4-mediated inflammation burst, demonstrating a cardioprotective effect in endotoxemia and polymicrobial sepsis. Our findings provide insight into the pathogenesis of endotoxemic cardiac dysfunction and suggest a novel approach for its treatment. TRPCs, nonselective cation channels, are involved in cardiac contraction and conduction. Here, the authors show that Trpc1/6 deficiency or pharmacological inhibition improves endotoxemic cardiac dysfunction and prolongs survival by prominently suppressing cardiac inflammation and ER Ca<superscript>2+</superscript> release. [ABSTRACT FROM AUTHOR]
- Subjects :
- HEART diseases
CARDIAC contraction
LEAKAGE
INFLAMMATION
HEART failure
RYANODINE
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 13
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Nature Communications
- Publication Type :
- Academic Journal
- Accession number :
- 160562730
- Full Text :
- https://doi.org/10.1038/s41467-022-35242-0