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 LPSinduced 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 Gp91 phox , 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.

Deletion of Protein Tyrosine Phosphatase 1B (PTP1B) Enhances Endothelial Cyclooxygenase 2 Expression and Protects Mice from Type 1 Diabetes-Induced Endothelial Dysfunction

“…This suggested a direct role for PTP1B in the control of endothelial relaxation. A similar role for PTP1B has previously been suggested by the group of Vincent Richard who demonstrated that deletion or pharmacological inhibition of PTP1B prevented heart failure- or sepsis-induced endothelial dysfunction [ 10 , 23 ]. The authors of the latter studies argued for a direct beneficial effect of PTP1B inhibitors on endothelial function.…”

Assessment of endothelial damage and cardiac injury in a mouse model mimicking thrombotic thrombocytopenic purpura

“…First, as suggested by convincing evidence that early endothelial dysfunction, and especially alteration of eNOS-mediated production of NO, plays a major role in endothelial dysfunction leading to cardiac dysfunction [41], we confirmed that induction of TMA decreased eNOS mRNA expression in cardiac ventricles. This unreported effect may be worsened by the widespread microthrombi that may be responsible for tissue hypoxia, which is known to decrease eNOS expression [42,43].…”

Protein S‐sulfhydration by hydrogen sulfide in cardiovascular system

“…Protein tyrosine phosphatase 1B (PTP1B) plays a vital role in endoplasmic reticulum (ER) stress and is regarded as a potential target for therapeutic intervention in obesity‐induced cardiomyopathy (Kandadi et al, ) and septic shock‐induced cardiovascular dysfunction (Coquerel et al, ). Krishnan et al found that H 2 S induced PTP1B S‐sulfhydration at Cys 215 to inhibit its activity, which facilitated phosphorylation and activation of protein kinase‐like ER kinase, and promoted restoration of ER homeostasis.…”