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p38α regulates SERCA2a function.

Leena Kaikkonen¹, Johanna Magga¹, Veli-Pekka Ronkainen²

¹Dept. of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, P.O. BOX 5000, FI-90014 Oulu, Finland.

Journal of Molecular and Cellular Cardiology

|December 24, 2013

Summary

Inhibiting p38α in the heart enhances phospholamban (PLB) phosphorylation, improving calcium handling and cardiac contractility. This study reveals a new mechanism for regulating heart function through p38 pathway modulation.

Keywords:

AMVM ARVM Cardiac contractility ET-1 G protein coupled receptor kinase GRK I-1 MAPK NRVM OA PLB PP1 PP2A Phospholamban SERCA2a adult mouse ventricular myocyte adult rat ventricular myocyte dn dominant negative endothelin-1 inhibitor-1 mitogen-activated protein kinase neonatal rat ventricular myocyte okadaic acid p38 phospholamban protein phosphatase-1 protein phosphatase-2A sarco/endoplasmic reticulum Ca(2+) ATPase

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Area of Science:

Cardiovascular Physiology
Molecular Cardiology
Cell Signaling

Background:

Cardiac contractility is modulated by cAMP-dependent protein kinase (PKA) and p38 mitogen-activated protein kinase (MAPK).
p38 MAPK acts as a negative regulator of cardiac contractile function.
Understanding p38's role is crucial for identifying therapeutic targets.

Purpose of the Study:

To elucidate the molecular mechanisms underlying the positive inotropic effect of p38 inhibition.
To investigate how p38 signaling influences cardiac contractility.

Main Methods:

Utilized isolated adult and neonatal cardiomyocytes and perfused rat hearts.
Employed chemical p38 inhibition, dominant-negative p38α, and p38α RNA interference (RNAi).
Assessed phospholamban (PLB) phosphorylation, Ca(2+)-transient decay, and sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) function.

Main Results:

p38 inhibition, specifically p38α, enhanced PLB phosphorylation.
Reduced Ca(2+)-transient decay time indicated improved SERCA function and increased cardiomyocyte contractility.
p38 inhibition decreased protein phosphatase 2A (PP2A) activity, leading to protein phosphatase inhibitor-1 (I-1) phosphorylation and PP1 inhibition.

Conclusions:

Inhibition of p38α promotes PLB phosphorylation and enhances diastolic Ca(2+) uptake.
This study identifies a novel mechanism regulating cardiac contractility via p38 pathway modulation.
Findings suggest p38α as a potential therapeutic target for enhancing cardiac function.