more Inhibition of aldosterone synthase, the key enzyme in aldosterone formation, could be an alternative strategy for mineralocorticoid-receptor antagonists in congestive heart failure (CHF), but its effect in CHF is unknown. Inhibition of aldosterone synthase, the key enzyme in aldosterone formation, could be an alternat. PTP1B is an attractive target for the treatment of sepsis. 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 deletion also improved survival in a cecal ligation puncture model of sepsis. Finally, PTP1B(-/-) mice displayed a markedly reduced LPS-induced mortality, an effect also observed using a pharmacological PTP1B inhibitor. PTP1B deficiency also reduced cardiac P38 and extracellular signal-regulated protein kinase 1 and 2 phosphorylation and increased phospholamban phosphorylation. 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 gene deletion also limited LPS-induced cardiac dysfunction assessed by echocardiography, left ventricular pressure-volume curves, and in isolated perfused hearts. 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. 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.
PTP1B(-/-) or wild-type mice received LPS (15 mg/kg) or vehicle followed by subcutaneous fluid resuscitation (saline, 30 mL/kg). Thus, we explored the beneficial therapeutic effect of PTP1B gene deletion on lipopolysaccharide (LPS)-induced cardiovascular dysfunction, inflammation, and mortality. However, the cardiovascular effect of PTP1B invalidation in sepsis is unknown. 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.
more Cardiovascular dysfunction is a major cause of mortality in patients with sepsis. Cardiovascular dysfunction is a major cause of mortality in patients with sepsis.
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