Circulation research · 2012
Cardiotoxic and cardioprotective features of chronic β-adrenergic signaling.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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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 Kevin Yang, Chen Xiongwen
Аннотация
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.
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.
Предметные рубрики MeSH
Adrenergic beta-AntagonistsAnimalsApoptosisCalciumCalcium-Calmodulin-Dependent Protein Kinase Type 2CardiomegalyCatsCells, CulturedCyclic AMPCyclic AMP-Dependent Protein KinasesCytosolDisease Models, AnimalDose-Response Relationship, DrugEnzyme ActivationExtracellular Signal-Regulated MAP KinasesFibrosisGreen Fluorescent ProteinsHeart FailureIntracellular Signaling Peptides and ProteinsIsoproterenolMiceMice, TransgenicMyocytes, CardiacReceptors, Adrenergic, betaRecombinant Fusion ProteinsSarcoplasmic ReticulumSignal TransductionStroke VolumeTime FactorsTransfectionrac GTP-Binding Proteinsrap1 GTP-Binding Proteins