| First Author | Tang N | Year | 2022 |
| Journal | Nat Commun | Volume | 13 |
| Issue | 1 | Pages | 7455 |
| PubMed ID | 36460692 | Mgi Jnum | J:334628 |
| Mgi Id | MGI:7410282 | Doi | 10.1038/s41467-022-35242-0 |
| Citation | Tang N, et al. (2022) TRPC channels blockade abolishes endotoxemic cardiac dysfunction by hampering intracellular inflammation and Ca(2+) leakage. Nat Commun 13(1):7455 |
| abstractText | Intracellular Ca(2+) dysregulation is a key marker in septic cardiac dysfunction; however, regulation of the classic Ca(2+) 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(2+) 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(2+) 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. |
