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Protection against TNF-induced lethal shock by soluble guanylate cyclase inhibition requires functional inducible
A Cauwels1, W Van Molle, B Janssen
1MPET, Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology, Ghent University, Belgium. anje@dmb.rug.ac.be
Abstract:
Hypotension and shock observed in sepsis, SIRS, and tumor necrosis factor (TNF) or cytokine-based cancer treatment are the consequence of excessive nitric oxide (NO) production and subsequent soluble guanylate cyclase (sGC)-mediated vascular smooth muscle relaxation. We demonstrate here that, while NO synthase (NOS) inhibitors exacerbated toxicity, inhibitors of sGC activation protected against TNF-induced lethality, bradycardia, and hypotension. Importantly, sGC inhibition did not interfere with the antitumor activity of TNF. Using NOS inhibitors or iNOS-deficient animals, we furthermore observed that no protection against TNF toxicity could be obtained in the absence of NO. These data imply that iNOS- (and not eNOS-) derived NO is an endogenous protective molecule indispensable to survive a TNF challenge and exerting this beneficial effect via sGC-independent mechanisms.
Insights
Inhibiting soluble guanylate cyclase (sGC) protected against tumor necrosis factor (TNF) toxicity, but nitric oxide (NO) synthase (NOS) inhibitors worsened it. NO derived from inducible NOS (iNOS) protects against TNF, independent of sGC.
Area of Science:
- Immunology
- Pharmacology
- Molecular Biology
Background:
- Sepsis, SIRS, and cancer treatments involving tumor necrosis factor (TNF) can cause hypotension and shock.
- This is linked to excessive nitric oxide (NO) production, leading to vascular smooth muscle relaxation via soluble guanylate cyclase (sGC).
Purpose of the Study:
- To investigate the role of NO and sGC in TNF-induced toxicity.
- To determine if targeting sGC can mitigate TNF toxicity without affecting its anti-tumor effects.
Main Methods:
- Administered NO synthase (NOS) inhibitors and sGC inhibitors to animals.
- Utilized iNOS-deficient animals.
- Assessed lethality, bradycardia, hypotension, and anti-tumor activity of TNF.
Main Results:
- NOS inhibitors exacerbated TNF toxicity.
- sGC inhibitors protected against TNF-induced lethality, bradycardia, and hypotension.
- sGC inhibition did not impair the anti-tumor effects of TNF.
- Protection against TNF toxicity was absent without NO, indicating NO's protective role.
- Inducible NOS (iNOS)-derived NO, not endothelial NOS (eNOS)-derived NO, is crucial for protection.
Conclusions:
- iNOS-derived NO is an endogenous protective factor against TNF challenge.
- This protective effect is mediated through sGC-independent mechanisms.
- Targeting sGC is a potential therapeutic strategy for managing TNF-induced hypotension and shock without compromising anti-tumor efficacy.