Abstract 163: Protein Phosphatase Type 1 Induces Depressed Cardiac Function Via Microtubule Network Densification
Type 1 protein phosphatase (PP1), a major cardiac Ser/Thr protein phosphatase isotype, is hyperactivated in the failing heart. Activated PP1 may induce cardiac dysfunction, at least in part through effects on calcium metabolism. A second abnormality of the failing heart is increased density of the cardiocyte microtubule (MT) network, caused in part by increased binding of microtubule-associated protein 4 (MAP4) to MTs. This abnormality is known to cause contractile dysfunction via viscous loading in severe pressure overload cardiac hypertrophy and failure. Since increased PP1 activity could dephosphorylate MAP4, which enhances MAP4 affinity for microtubule and thus microtubule assembly and stability, our hypothesis is that active PP1 may be causally linked to depressed cardiac function via microtubule network densification. To test this idea, we used transgenic mice having cardiac-restricted overexpression of the catalytic subunit of PP1 ( Mol Cell Biol. 2002;22:4124–35), wherein myocardial PP1 activity is increased ~3-fold. In these mice, the polymerized fraction of cardiac αβ-tubulin heterodimers was 1.5-fold higher than in same-strain WT controls. Consistent with this, microtubule network density via confocal microscopy was substantially greater in transgenic versus WT cardiocytes. To determine the effects of active PP1 on cardiac MT stability, colchicine (0.5 mg/kg, i.p.) was given to the mice. At 4 hours, the polymerized αβ-tubulin heterodimer fraction was significantly increased in PP1 overexpressing cardiocytes. Thus, increased activity of PP1 appears to increase MAP4 microtubule affinity, which in turn generates a dense network of stabilized microtubules. This cytoskeletal abnormality, which inhibits cardiac contraction, represents a second potential mechanism for the deleterious effects of PP1 overactivity on the heart.