Cardiotoxic and cardioprotective features of chronic β-Adrenergic signaling

Xiaoying Zhang, Christopher Szeto, Erhe Gao, Mingxin Tang, Jianguo Jin, Qin Fu, Catherine Makarewich, Xiaojie Ai, Ying Li, Allen Tang, Jenny Wang, Hui Gao, Fang Wang, Xinyi Joy Ge, Satya P. Kunapuli, Lin Zhou, Chunyu Zeng, Yang Kevin Xiang, Xiongwen Chen

Research output: Contribution to journalArticle

81 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)498-509
Number of pages12
JournalCirculation Research
Volume112
Issue number3
DOIs
StatePublished - Feb 1 2013

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Cyclic AMP-Dependent Protein Kinases
Adrenergic Agents
Muscle Cells
Calcium-Calmodulin-Dependent Protein Kinases
Adrenergic Receptors
Calcium
Adrenergic Agonists
Felidae
Extracellular Signal-Regulated MAP Kinases
Cardiomegaly
Sarcoplasmic Reticulum
Isoproterenol
Cardiac Myocytes
Transgenic Mice
Cause of Death
Fibrosis
Cell Death
Heart Failure
Myocardial Infarction
Apoptosis

Keywords

  • apoptosis
  • Ca2+/calmodulin-dependent protein kinase II
  • cAMP
  • exchange protein directly activated by cAMP
  • extracellular signal-regulated kinases 1/2
  • protein kinase A inhibition

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Zhang, X., Szeto, C., Gao, E., Tang, M., Jin, J., Fu, Q., ... Chen, X. (2013). Cardiotoxic and cardioprotective features of chronic β-Adrenergic signaling. Circulation Research, 112(3), 498-509. https://doi.org/10.1161/CIRCRESAHA.112.273896

Cardiotoxic and cardioprotective features of chronic β-Adrenergic signaling. / Zhang, Xiaoying; Szeto, Christopher; Gao, Erhe; Tang, Mingxin; Jin, Jianguo; Fu, Qin; Makarewich, Catherine; Ai, Xiaojie; Li, Ying; Tang, Allen; Wang, Jenny; Gao, Hui; Wang, Fang; Ge, Xinyi Joy; Kunapuli, Satya P.; Zhou, Lin; Zeng, Chunyu; Xiang, Yang Kevin; Chen, Xiongwen.

In: Circulation Research, Vol. 112, No. 3, 01.02.2013, p. 498-509.

Research output: Contribution to journalArticle

Zhang, X, Szeto, C, Gao, E, Tang, M, Jin, J, Fu, Q, Makarewich, C, Ai, X, Li, Y, Tang, A, Wang, J, Gao, H, Wang, F, Ge, XJ, Kunapuli, SP, Zhou, L, Zeng, C, Xiang, YK & Chen, X 2013, 'Cardiotoxic and cardioprotective features of chronic β-Adrenergic signaling', Circulation Research, vol. 112, no. 3, pp. 498-509. https://doi.org/10.1161/CIRCRESAHA.112.273896
Zhang, Xiaoying ; Szeto, Christopher ; Gao, Erhe ; Tang, Mingxin ; Jin, Jianguo ; Fu, Qin ; Makarewich, Catherine ; Ai, Xiaojie ; Li, Ying ; Tang, Allen ; Wang, Jenny ; Gao, Hui ; Wang, Fang ; Ge, Xinyi Joy ; Kunapuli, Satya P. ; Zhou, Lin ; Zeng, Chunyu ; Xiang, Yang Kevin ; Chen, Xiongwen. / Cardiotoxic and cardioprotective features of chronic β-Adrenergic signaling. In: Circulation Research. 2013 ; Vol. 112, No. 3. pp. 498-509.
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AU - Fu, Qin

AU - Makarewich, Catherine

AU - Ai, Xiaojie

AU - Li, Ying

AU - Tang, Allen

AU - Wang, Jenny

AU - Gao, Hui

AU - Wang, Fang

AU - Ge, Xinyi Joy

AU - Kunapuli, Satya P.

AU - Zhou, Lin

AU - Zeng, Chunyu

AU - Xiang, Yang Kevin

AU - Chen, Xiongwen

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AB - 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 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.

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