Format

Send to

Choose Destination
See comment in PubMed Commons below
Circ Res. 2013 Feb 1;112(3):498-509. doi: 10.1161/CIRCRESAHA.112.273896. Epub 2012 Oct 25.

Cardiotoxic and cardioprotective features of chronic β-adrenergic signaling.

Author information

1
Cardiovascular Research Center, Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA.

Abstract

RATIONALE:

In the failing heart, persistent β-adrenergic receptor activation is thought to induce myocyte death by protein kinase A (PKA)-dependent and PKA-independent activation of calcium/calmodulin-dependent kinase II. β-adrenergic signaling pathways also are capable of activating cardioprotective mechanisms.

OBJECTIVE:

This study used a novel PKA inhibitor peptide to inhibit PKA activity to test the hypothesis that β-adrenergic receptor signaling causes cell death through PKA-dependent pathways and cardioprotection through PKA-independent pathways.

METHODS AND RESULTS:

In PKA inhibitor peptide transgenic mice, chronic isoproterenol failed to induce cardiac hypertrophy, fibrosis, and myocyte apoptosis, and decreased cardiac function. In cultured adult feline ventricular myocytes, PKA inhibition protected myocytes from death induced by β1-adrenergic receptor agonists by preventing cytosolic and sarcoplasmic reticulum Ca(2+) overload and calcium/calmodulin-dependent kinase II activation. PKA inhibition revealed a cardioprotective role of β-adrenergic signaling via cAMP/exchange protein directly activated by cAMP/Rap1/Rac/extracellular signal-regulated kinase pathway. Selective PKA inhibition causes protection in the heart after myocardial infarction that was superior to β-blocker therapy.

CONCLUSIONS:

These results suggest that selective block of PKA could be a novel heart failure therapy.

PMID:
23104882
PMCID:
PMC3562387
DOI:
10.1161/CIRCRESAHA.112.273896
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center