Mechanisms of systolic heart failure in PP2CxPP5 double transgenic mice.

The function importance of serine threonine phosphatases (PP) in the heart is still subject of investigations. For instance, PP5 and PP2C occur in the human heart. It is unclear how they interact in the human heart. In order to obtain a model system, we have crossbred mice with heart-specific overexpression of PP2C or PP5 to obtain wild-type mice (WT), PP2C transgenic mice (PP2C-TG), PP5 transgenic mice (PP5-TG), and PP2CxPP5 double transgenic mice (DT). Moreover, while PP2C-TG and PP5-TG did not show any increase in relative heart weight, it was increased in DT. In histology, DT showed cardiac fibrosis based on Masson/Goldner staining compared to WT. Basal ejection fraction was reduced in PP5-TG by 25%, by 29% in PP2C-TG, and by 38% of WT values in DT. This went hand in hand with a diminished phosphorylation of phospholamban at serine-16, the phosphorylation site for the cAMP-dependent protein kinase (PKA), after perfusion of isolated hearts with isoprenaline. DT and PP2C-TG sustained ischemia and reperfusion of isolated hearts worse than WT or PP5-TG. Expression of atrial natriuretic factor (ANF, marker of hypertrophy), of collagen 1a (fibrosis marker) and nuclear factor kappa B (marker of inflammation) in DT were augmented versus WT (ANF: 5.14 ± 0.75 vs. 1.00 ± 0.33; Col1a1: 1.82 ± 0.09 vs. 1.00 ± 0.10; Nfkb1: 1.33 ± 0.03 vs 1.00 ± 0.04; n = 6-10; p < 0.05). In summary, cardiac co-overexpression of two PPs, namely, PP2C and PP5, was detrimental to cardiac function. The underlying (patho)mechanism for this may involve dephosphorylation of Ca2+ regulatory proteins but also accompanying fibrosis and inflammation.