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.

BackgroundImproving sepsis support is one of the three pillars of a 2017 resolution according to the World Health Organization (WHO). Septic shock is indeed a burden issue in the intensive care units. Hemodynamic stabilization is a cornerstone element in the bundle of supportive treatments recommended in the Surviving Sepsis Campaign (SSC) consecutive biannual reports.Main bodyThe “Pandera’s box” of septic shock hemodynamics is an eternal debate, however, with permanent contentious issues. Fluid resuscitation is a prerequisite intervention for sepsis rescue, but selection, modalities, dosage as well as duration are subject to discussion while too much fluid is associated with worsen outcome, vasopressors often need to be early introduced in addition, and catecholamines have long been recommended first in the management of septic shock. However, not all patients respond positively and controversy surrounding the efficacy-to-safety profile of catecholamines has come out. Preservation of the macrocirculation through a “best” mean arterial pressure target is the actual priority but is still contentious. Microcirculation recruitment is a novel goal to be achieved but is claiming more knowledge and monitoring standardization. Protection of the cardio-renal axis, which is prevalently injured during septic shock, is also an unavoidable objective. Several promising alternative or additive drug supporting avenues are emerging, trending toward catecholamine’s sparing or even “decatecholaminization.” Topics to be specifically addressed in this review are: (1) mean arterial pressure targeting, (2) fluid resuscitation, and (3) hemodynamic drug support.ConclusionImproving assessment and means for rescuing hemodynamics in early septic shock is still a work in progress. Indeed, the bigger the unresolved questions, the lower the quality of evidence.