Genetic Disruption Of Protein Tyrosine Phosphatase 1b Attenuates Both Myocardial And Endothelial Dysfunction In Mice With Heart Failure

We have shown previously that chronic, in vivo pharmacological inhibition of protein tyrosine phosphatase 1B (PTP1B) prevented both endothelial and cardiac dysfunction in mice with chronic heart failure (CHF). The present study was designed to test whether similar cardiovascular protective effects are present in mice genetically deficient for PTP1B. CHF was induced by coronary ligation, either in wild type (WT) or PTP1B deficient (PTP1B-/-) BALB/c mice. After 2 months of ligation, echocardiographic analysis of left ventricular (LV) function and remodelling was performed, after which flow-mediated, NO-dependent vasodilatation (FMD) of mesenteric resistance arteries was evaluated. In PTP1B-/- mice with CHF (n = 13), compared to CHF WT mice (n = 15) LV end diastolic diameter (LVEDD) and LV end systolic diameter (LVESD) were reduced (LVEDD: CHF WT 6.1 ± 0.2; CHF PTP1B-/- 5.2 ± 0.2 mm, p < 0.01; LVESD: CHF WT 5.5 ± 0.2; CHF PTP1B-/- 3.9 ± 0.3 mm, p<0.01), while fractional shortening (FS) and cardiac output (CO) were increased (FS: CHF WT 10.9 ± 1.6; CHF PTP1B-/- 22.7 ± 2.5 %, p < 0.01; CO: WT 16.3 ± 1.0; PTP1B-/- 22.2 ± 1.1 ml/min, p < 0.05). Genetic disruption of PTP1B was also associated with decreased collagen density. These hemodynamic and structural effects were observed in the context of identical infarct sizes. Vascular studies showed that compared to CHF WT mice (n=15), CHF PTP1B-/- mice (n = 16) displayed an increased FMD (CHF WT 5 ± 1, CHF PTP1B-/- 19 ± 4 %, p < 0.05). Additionally, in vitro downregulation of PTP1B (by a 3 day incubation with shRNA) also increased FMD in arteries isolated from CHF mice (max FMD; untreated: 6 ± 2; scrambled shRNA: 7 ± 2; PTP1B shRNA 27 ± 2 %, p < 0.01). Thus, genetic disruption of PTP1B prevent endothelial and cardiac dysfunction in CHF mice, suggesting that this enzyme may be a new interesting target for the treatment of CHF.