Gene deletion of protein tyrosine phosphatase 1B protects against sepsis-induced cardiovascular dysfunction and mortality.

Abstract

OBJECTIVE:

Cardiovascular dysfunction is a major cause of mortality in patients with sepsis. Recently, we showed that gene deletion or pharmacological inhibition of protein tyrosine phosphatase 1B (PTP1B) improves endothelial dysfunction and reduces the severity of experimental heart failure. However, the cardiovascular effect of PTP1B invalidation in sepsis is unknown. Thus, we explored the beneficial therapeutic effect of PTP1B gene deletion on lipopolysaccharide (LPS)-induced cardiovascular dysfunction, inflammation, and mortality.

APPROACH AND RESULTS:

PTP1B(-/-) or wild-type mice received LPS (15 mg/kg) or vehicle followed by subcutaneous fluid resuscitation (saline, 30 mL/kg). α-1-dependent constriction and endothelium-dependent dilatation, assessed on isolated perfused mesenteric arteries, were impaired 8 hours after LPS and significantly improved in PTP1B(-/-) mice. This was associated with reduced vascular expression of interleukin1-β, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, cyclooxygenase-2, and inducible nitric oxide synthase mRNA. PTP1B gene deletion also limited LPS-induced cardiac dysfunction assessed by echocardiography, left ventricular pressure-volume curves, and in isolated perfused hearts. PTP1B(-/-) mice also displayed reduced LPS-induced cardiac expression of tumor necrosis factor-α, interleukin1-β, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and Gp91phox, as well as of several markers of cellular infiltration. PTP1B deficiency also reduced cardiac P38 and extracellular signal-regulated protein kinase 1 and 2 phosphorylation and increased phospholamban phosphorylation. Finally, PTP1B(-/-) mice displayed a markedly reduced LPS-induced mortality, an effect also observed using a pharmacological PTP1B inhibitor. PTP1B deletion also improved survival in a cecal ligation puncture model of sepsis.

CONCLUSIONS:

PTP1B gene deletion protects against septic shock-induced cardiovascular dysfunction and mortality, and this may be the result of the profound reduction of cardiovascular inflammation. PTP1B is an attractive target for the treatment of sepsis.

• Authors: David Coquerel, Remi Neviere, Eugenie Delile, Paul Mulder, Xavier Marechal, David Montaigne, Sylvanie Renet, Isabelle Remy-Jouet, Elodie Gomez, Jean-Paul Henry, Jean-Claude do Rego, Vincent Richard, Fabienne Tamion
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 34 Issue 5 Pg. 1032-44 (May 2014) ISSN: 1524-4636 [Electronic] United States
• PMID: 24578383 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Icam1 protein, mouse
• Interleukin-1beta
• Lipopolysaccharides
• Membrane Glycoproteins
• RNA, Messenger
• Vascular Cell Adhesion Molecule-1
• lipopolysaccharide, E coli O55-B5
• Intercellular Adhesion Molecule-1
• Nitric Oxide
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• Cybb protein, mouse
• NADPH Oxidase 2
• NADPH Oxidases
• Mapk1 protein, mouse
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• p38 Mitogen-Activated Protein Kinases
• Protein Tyrosine Phosphatase, Non-Receptor Type 1
• Ptpn1 protein, mouse

Topics

• Animals
• Blood Pressure
• Cardiovascular Diseases (enzymology, genetics, physiopathology, prevention & control)
• Cecum (microbiology, surgery)
• Cyclooxygenase 2 (genetics, metabolism)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation
• Heart Rate
• Intercellular Adhesion Molecule-1 (genetics, metabolism)
• Interleukin-1beta (genetics, metabolism)
• Ligation
• Lipopolysaccharides
• Membrane Glycoproteins (genetics, metabolism)
• Mesenteric Arteries (enzymology, physiopathology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Muscle, Smooth, Vascular (enzymology, physiopathology)
• Myocardium (enzymology)
• NADPH Oxidase 2
• NADPH Oxidases (genetics, metabolism)
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type II (genetics, metabolism)
• Phosphorylation
• Protein Tyrosine Phosphatase, Non-Receptor Type 1 (deficiency, genetics)
• Punctures
• RNA, Messenger (metabolism)
• Sepsis (chemically induced, complications, enzymology, genetics, microbiology)
• Signal Transduction
• Time Factors
• Vascular Cell Adhesion Molecule-1 (genetics, metabolism)
• Vasodilation
• Ventricular Function, Left
• Ventricular Pressure
• p38 Mitogen-Activated Protein Kinases (metabolism)