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Updated: Jul 9, 2026
Transverse Aortic Constriction in Mice
Published on: April 21, 2010
Mechanisms of systolic heart failure in PP2CxPP5 double transgenic mice
Rebecca Schwarz1, Katarina Hadova2, Jan Klimas2
1Institute for Pharmacology and Toxicology, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
Abstract:
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.
Insights
Co-overexpression of protein phosphatases PP2C and PP5 in the heart detrimentally impacts cardiac function, leading to fibrosis and inflammation. This study investigates their detrimental interaction in transgenic mice, revealing impaired heart function and reduced ejection fraction.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- The roles of serine/threonine phosphatases (PP), specifically PP5 and PP2C, in cardiac function are not fully understood.
- Investigating the interaction between PP5 and PP2C in the human heart is crucial for understanding cardiac pathophysiology.
Purpose of the Study:
- To investigate the functional consequences of co-overexpressing PP2C and PP5 in the heart.
- To establish a model system for studying the combined effects of PP2C and PP5 in cardiac tissue.
Main Methods:
- Generation of wild-type (WT), PP2C-transgenic (PP2C-TG), PP5-transgenic (PP5-TG), and double-transgenic (DT) mice with heart-specific overexpression.
- Histological analysis (Masson/Goldner staining) to assess cardiac fibrosis.
- Measurement of ejection fraction and phospholamban phosphorylation.
- Assessment of cardiac function under ischemia-reperfusion conditions.
- Gene expression analysis of markers for hypertrophy (ANF), fibrosis (Collagen 1a), and inflammation (NF-κB).
Main Results:
- Double transgenic (DT) mice exhibited increased heart weight and cardiac fibrosis compared to WT.
- Ejection fraction was significantly reduced in DT mice (38% of WT values), PP2C-TG (29%), and PP5-TG (25%).
- Diminished phospholamban phosphorylation at serine-16 was observed post-isoprenaline stimulation.
- DT and PP2C-TG mice showed worse outcomes during ischemia-reperfusion.
- Expression of ANF, Collagen 1a, and NF-κB was augmented in DT mice.
Conclusions:
- Cardiac co-overexpression of PP2C and PP5 is detrimental to cardiac function.
- Potential mechanisms include dephosphorylation of Ca2+ regulatory proteins, fibrosis, and inflammation.
- These findings highlight the complex interplay of phosphatases in maintaining cardiac health.
