In:
Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 113, No. suppl_1 ( 2013-08)
Abstract:
Rationale: p38 MAPK is a negative regulator of cardiac contractile function, but the underlying molecular mechanism is not well understood. Objective: To determine the molecular mechanism mediating the positive inotropic effect of p38 inhibition. Methods and Results: The effect of p38 inhibition on calcium regulatory proteins and calcium cycling was investigated in isolated neonatal and adult rodent cardiomyocytes using chemical inhibitors, recombinant adenoviruses and RNAi. Chemical inhibition of p38 enhanced phospholamban (PLB) phosphorylation at serine 16 residue. This was recapitulated with dominant negative p38α adenovirus and by p38α RNAi, but not with dominant negative p38β adenovirus. Chemical inhibition of p38 and dominant negative p38α resulted in significant decrease in Ca 2+ -transient decay time in adult rat cardiomyocytes. Inhibition of p38α, but not p38β, induced an increase in phosphorylation of protein phosphatase inhibitor-1 at the protein kinase A site threonine 35. Analysis of underlying mechanisms revealed that p38 inhibition increased phosphorylation of G protein-coupled receptor kinase 2 (GRK2), but not GRK3 or GRK5. p38 inhibition- induced PLB phosphorylation was abolished in cardiomyocytes overexpressing wild type GRK2. In contrast, increased PLB phosphorylation upon p38 inhibition was not reduced in cardiomyocytes overexpressing GRK2 harboring a non-phosphorylatable mutation in serine 670 residue. Finally, p38 inhibition-induced shortening of Ca 2+ -transient decay time was absent in cardiomyocytes overexpressing wild type GRK2. Conclusions: Inhibition of p38α regulates protein phosphatase inhibitor-1 resulting in increased PLB phosphorylation and enhanced SERCA2a function.
Type of Medium:
Online Resource
ISSN:
0009-7330
,
1524-4571
DOI:
10.1161/res.113.suppl_1.A163
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2013
detail.hit.zdb_id:
1467838-X
Permalink
