Induction of Cardiac Fibrosis by β-Blocker in G Protein-independent and G Protein-coupled Receptor Kinase 5/β-Arrestin2-dependent Signaling Pathways

Nakaya, Michio; Chikura, Satsuki; Watari, Kenji; Mizuno, Natsumi; Mochinaga, Koji; Mangmool, Supachoke; Koyanagi, Satoru; Ohdo, Shigehiro; Sato, Yoji; Ide, Tomomi; Nishida, Motohiro; Kurose, Hitoshi

doi:10.1074/jbc.m112.357871

Cited by 54 publications

(50 citation statements)

References 50 publications

(61 reference statements)

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“…Metoprolol has also been shown to be a biased ligand for β 1 -ARs, in a pathway that appears to be different from carvedilol. 49 In a previous study, 3 we found absolutely no differences between metoprolol and carvedilol for the 6 mRNAs measure by qPCR. In the current study, there were some differences between the carvedilol and the combined metoprolol groups, 50 but none of them changed the statistical results of the metoprolol groups when the carvedilol data were added.…”

Section: Limitationsmentioning

confidence: 60%

Therapeutic Molecular Phenotype of β-Blocker–Associated Reverse-Remodeling in Nonischemic Dilated Cardiomyopathy

Kao

Lowes

Gilbert

et al. 2015

Circ Cardiovasc Genet

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volume) to the degree of eccentric hypertrophy (end-diastolic volume [EDV]). IDC in humans is associated with myocardial gene expression changes affecting contractile function and hypertrophy.2,3 Among these are upregulation in mRNA and protein abundances of β-myosin heavy chain (MYH7) and atrial natriuretic peptide (NPPA) with downregulation of α-myosin heavy chain (MYH6) and sarcoplasmic reticulum calcium-ATPase 2 (ATP2A2), a pattern also observed during fetal cardiac development.2,3 Reversal of these pathological changes is associated with ventricular reverse-remodeling in response to both β 1 -selective and nonselective β-adrenergic Background-When β-blockers produce reverse-remodeling in idiopathic dilated cardiomyopathy, they partially reverse changes in fetal-adult/contractile protein, natriuretic peptide, SR-Ca 2+ -ATPase gene program constituents. The objective of the current study was to further test the hypothesis that reverse-remodeling is associated with favorable changes in myocardial gene expression by measuring additional contractile, signaling, and metabolic genes that exhibit a fetal/adult expression predominance, are thyroid hormone-responsive, and are regulated by β 1 -adrenergic receptor signaling. A secondary objective was to identify which of these putative regulatory networks is most closely associated with observed changes. Methods and Results-Forty-seven patients with idiopathic dilated cardiomyopathy (left ventricular ejection fraction, 0.24±0.09) were randomized to the adrenergic-receptor blockers metoprolol (β 1-selective), metoprolol+doxazosin (β 1 /α 1 ), or carvedilol (β 1 /β 2 /α 1 ). Serial radionuclide ventriculography and endomyocardial biopsies were performed at baseline, 3, and 12 months. Expression of 50 mRNA gene products was measured by quantitative polymerase chain reaction. Thirty-one patients achieved left ventricular ejection fraction reverse-remodeling response defined as improvement by ≥0.08 at 12 months or by ≥0.05 at 3 months (Δ left ventricular ejection fraction, 0.21±0.10). Changes in gene expression in responders versus nonresponders were decreases in NPPA and NPPB and increases in MYH6, ATP2A2, PLN, RYR2, ADRA1A, ADRB1, MYL3, PDFKM, PDHX, and CPT1B. All except PDHX involved increase in adult or decrease in fetal cardiac genes, but 100% were concordant with changes predicted by inhibition of β 1 -adrenergic signaling. Conclusions-In addition to known gene expression changes, additional calcium-handling, sarcomeric, adrenergic signaling, and metabolic genes were associated with reverse-remodeling. The pattern suggests a fetal-adult paradigm but may be because of reversal of gene expression controlled by a β 1 -adrenergic receptor gene network. Clinical Trial Registration-URL: www.clinicaltrials.gov. Unique Identifier: NCT01798992.

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Section: Limitationsmentioning

confidence: 60%

Therapeutic Molecular Phenotype of β-Blocker–Associated Reverse-Remodeling in Nonischemic Dilated Cardiomyopathy

Kao

Lowes

Gilbert

et al. 2015

Circ Cardiovasc Genet

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“…Second, previous reports showed that AngII-induced responses in cardiac fibroblasts and other fibroblast cell lines are different from those in cardiomyocytes in many aspects (9,19), which has led us to assume that SII-induced responses in fibroblast cell lines will be different from SII-induced responses in cardiomyocytes. Third, although -arrestin-biased agonists promote cardiomyocyte protection and reduce cardiac fibrosis (20), -arrestin signaling in different types of fibroblasts have been reported to initiate tissue fibrosis (21), and our own studies have found that -arrestin2 mediates metoprolol-stimulated cardiac fibrosis in vivo (22). Thus, SII may activate AT1R--arrestin signaling in cardiac fibroblasts and initiate cardiac fibrosis in the heart that could lead to cardiac dysfunction.…”

Section: Introductionmentioning

confidence: 79%

“…blocker metoprolol induces cardiac fibrosis through -arrestin2 (22). Another report also mentioned that -arrestins mediate fibroblast invasion and the development of pulmonary fibrosis (21).…”

Section: Discussionmentioning

confidence: 99%

Ezrin, Radixin, and Moesin Phosphorylation in NIH3T3 Cells Revealed Angiotensin II Type 1 Receptor Cell-Type–Dependent Biased Signaling

2013

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Abstract. -Arrestin-biased agonists are a new class of drugs with promising therapeutic effects. The molecular mechanisms of -arrestin-biased agonists are still not completely identified. Here, we investigated the effect of angiotensin II (AngII) and [Sar1,Ile4,Ile8] AngII (SII), a -arrestinbiased agonist, on ezrin-radixin-moesin (ERM) phosphorylation in NIH3T3 cells (a fibroblast cell line) stably expressing AngII type 1A receptor. ERM proteins are cross-linkers between the plasma membrane and the actin cytoskeleton and control a number of signaling pathways. We also investigated the role of Gq protein and -arrestins in mediating ERM phosphorylation. We found that AngII stimulates ERM phosphorylation by acting as a -arrestin-biased agonist and AngIIstimulated ERM phosphorylation is mediated by -arrestin2 not -arrestin1. We also found that SII inhibits ERM phosphorylation by acting as a Gq protein-biased agonist. We concluded that ERM phosphorylation is a unique -arrestin-biased agonism signal. Both AngII and SII can activate either Gq protein or -arrestin-mediated signaling as functional biased agonists according to the type of the cell on which they act.

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“…To evaluate the conformational change of GRK6, a bioluminescence resonance energy transfer (BRET) experiment was performed, as previously described [17]. The plasmid of Rluc(h)-GRK6-GFP 2 was constructed and transfected into HEK293 cells.…”

Section: Bioluminescence Resonance Energy Transfer Assaymentioning

confidence: 99%

“…To monitor the structural change of GRK6, we developed an intramolecular BRET probe that detects this change. A similar intramolecular BRET probe has been used to analyze the conformational change of b-arrestins [17,19,20]. As shown in Fig.…”

Section: The Conformational Change Of Grk6 Is Induced By Tnf-a Stimulmentioning

confidence: 99%

GRK6 phosphorylates IκBα at Ser32/Ser36 and enhances TNF-α-induced inflammation

Ohba

Nakaya

Watari

et al. 2015

Biochemical and Biophysical Research Communications

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Induction of Cardiac Fibrosis by β-Blocker in G Protein-independent and G Protein-coupled Receptor Kinase 5/β-Arrestin2-dependent Signaling Pathways

Cited by 54 publications

References 50 publications

Therapeutic Molecular Phenotype of β-Blocker–Associated Reverse-Remodeling in Nonischemic Dilated Cardiomyopathy

Therapeutic Molecular Phenotype of β-Blocker–Associated Reverse-Remodeling in Nonischemic Dilated Cardiomyopathy

Ezrin, Radixin, and Moesin Phosphorylation in NIH3T3 Cells Revealed Angiotensin II Type 1 Receptor Cell-Type–Dependent Biased Signaling

GRK6 phosphorylates IκBα at Ser32/Ser36 and enhances TNF-α-induced inflammation

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