Research ArticleHeart Failure

Paroxetine-mediated GRK2 inhibition reverses cardiac dysfunction and remodeling after myocardial infarction

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Science Translational Medicine  04 Mar 2015:
Vol. 7, Issue 277, pp. 277ra31
DOI: 10.1126/scitranslmed.aaa0154
  • Fig. 1. Paroxetine treatment reverses LV dysfunction after MI.

    (A) Representative short-axis M-mode echocardiography recordings from C57BL/6 mice treated with vehicle (DMSO and water), fluoxetine (fluox), or paroxetine (parox) at baseline, 2 weeks (pretreatment) and 4 and 6 weeks after MI compared to noninfarcted (sham) mice treated the same way. (B and C) Serial measures of noted experimental groups for (B) LVEF and (C) FS. (D and E) Serial measures of (D) LVIDd and (E) LVIDs in these mice. (F) Serial measures of LVEDd in these mice. *P = 0.004, **P = 0.001, ***P < 0.0001 as determined by one-way analysis of variance (ANOVA) relative to corresponding MI vehicle. n = 9 to 14 per group.

  • Fig. 2. Paroxetine treatment after MI enhances in vivo LV hemodynamic function and restores βAR inotropic reserve.

    Hemodynamics were recorded from wild-type (WT) mice treated with vehicle, fluoxetine (fluox), or paroxetine (parox) at 6 weeks after MI (after 4 weeks of treatment) compared to sham. (A) Representative LV dP/dt hemodynamic recordings. Arrows mark administration of ISO. (B) Quantification of mean systemic pressure. (C to E) Quantification of (C) HR, (D) LV +dP/dt average maximum (*P = 0.0234 and 0.0130, **P = 0.0008, ***P ≤ 0.0001), and (E) LV −dP/dt average minimum at baseline and with increasing doses of ISO (0.1 to 10 ng) (*P = 0.0105 and 0.0134 for sham, and 0.0280 for MI; **P = 0.0058, 0.0040, and 0.0087, respectively). bpm, beats per minute. (F) Quantification of LVEDP at baseline (no ISO) 6 weeks after sham and MI (**P = 0.005). Statistics are relative to corresponding sham or MI vehicle by two- or one-way ANOVA as appropriate. n = 12 to 15 per group.

  • Fig. 3. Paroxetine reduces LV dilation and fibrosis after MI.

    (A to C) Measures of (A) HW normalized to TL, (B) HL normalized to TL, and (C) LW to TL in WT C57BL/6 mice treated with vehicle, fluoxetine (fluox), or paroxetine (parox) at 6 weeks after MI (4 weeks of treatment) compared to noninfarcted (sham) mice treated the same way. ***P ≤ 0.0001 relative to sham and tttP = 0.0075 relative to MI vehicle by one-way ANOVA. n = 12 to 19 per group. (D) Representative images of Masson’s trichrome–stained murine heart sections from WT mice treated with vehicle, fluox, or parox at 6 weeks after sham or MI surgery (4 weeks after treatment). (E and F) Graphic representation of (E) infarct length and (F) lumen area in vehicle-, fluox-, or parox-treated mice 6 weeks after MI. *P = 0.004 by one-way ANOVA. n = 7, 6, and 8, respectively, for (D) to (G). (G) Representative images of Masson’s trichrome–stained murine heart sections focusing on the border zone and the infarct area in vehicle-, fluox-, and parox-treated mice 6 weeks after MI.

  • Fig. 4. Paroxetine reduces SNS overdrive and restores the myocardial βAR system after MI.

    (A and B) Quantification of serum (A) epinephrine and (B) norepinephrine from WT mice, either sham or MI at 6 weeks, treated with vehicle, fluoxetine (fluox), or paroxetine (parox). (C) βAR density in sham versus 6-week post-MI hearts (Bmax values shown as femtomoles of receptor per milligram of sarcolemmal protein) with vehicle or parox treatment. (D) Representative Western blot image of GRK2 and GAPDH (glyceraldehyde-3-phosphate dehydrogenase) protein expression 6 weeks after sham or MI (after 4 weeks of treatment with vehicle, fluox, or parox). *P = 0.0167, 0.0047, 0.0427, and 0.0244, respectively (A and B), and *P = 0.0003 (C) versus sham vehicle and *P = 0.0119 versus MI parox by one-way ANOVA. n = 6 to 9 per group.

  • Fig. 5. Paroxetine’s efficacy in reversing HF is not additive when GRK2 is inhibited by βARKct but is maintained even in the face of forced GRK2 overexpression.

    (A) Measures of LVEF at 2 (left) and 6 (right) weeks after MI in TgβARKct or NLC mice treated with vehicle or paroxetine (parox) compared to sham animals. ***P < 0.0001 relative to sham; tP = 0.0004 or P < 0.0001 relative to NLC MI vehicle by one-way ANOVA of all 2-week or all 6-week data. (B and C) Measures of (B) HW and (C) LW normalized to TL in TgβARKct or NLC mice 6 weeks after MI compared to sham controls. **P = 0.0027; ***P = 0.0001 by one-way ANOVA. n = 4 to 8 per group. (D) Measures of LVEF at 2 (left) and 6 (right) weeks after MI in TgGRK2 or NLC mice treated with vehicle or parox compared to sham animals. **P = 0.0001, 0.0019, 0.0016, 0.0138, and 0.0019, respectively, relative to NLC MI vehicle or parox; ***P < 0.0001 relative to sham by one-way ANOVA of all 2-week or all 6-week data. ns, not significant. (E and F) Measures of (E) HW/TL and (F) LW/TL in TgGRK2 or NLC mice 6 weeks after MI compared to sham controls. *P = 0.0121 (E), 0.0412 (F); **P = 0.0025; ***P < 0.0001 by one-way ANOVA. n = 5 to 11 per group.

  • Fig. 6. Paroxetine’s beneficial effect in post-MI HF is maintained after termination of treatment.

    C57BL/6 mice treated with vehicle (DMSO and water) or paroxetine (parox) at baseline, 2, 4, 6, and 8 weeks after procedure (sham and MI). Two weeks after surgery, these mice were treated with vehicle or paroxetine (parox) for 4 weeks (weeks 2 to 6), followed by an additional 2 weeks of no treatment (weeks 6 to 8). (A) Serial measures of noted experimental groups for LVEF. (B) Quantification of LV +dP/dt average maximum at baseline and with increasing doses of ISO (0.1 to 10 ng) in these mice. (C and D) Measures of (C) HW/TL and (D) LW/TL in these mice. (E and F) Quantification of serum (E) epinephrine and (F) norepinephrine in these mice. *P = 0.0461; **P ≤ 0.0009 for (B) sham and (E); **P = 0.0072 for (B) MI and 0.0024 for (F); and ***P ≤ 0.001 versus corresponding sham or MI by one- or two-way ANOVA as appropriate. n = 9 to 15 per group [(A) to (D)], n = 4 to 5 per group for serum catecholamines.

  • Fig. 7. Paroxetine is more effective at reversing post-MI HF than β-blocker therapy alone.

    (A and B) Serial measures of LVEF (A) and FS (B) from WT mice treated with vehicle, metoprolol (met), paroxetine (parox), or metoprolol and paroxetine concurrently after MI compared to vehicle-treated mice. **P = 0.0011 and ***P < 0.001 by one-way ANOVA for post-MI parox and met + parox or met relative to corresponding MI vehicle and met. (C and D) Serial measures of (C) LVIDd and (D) LVIDs in these animals compared to sham mice. *P = 0.0012 parox and 0.0047 m + p (4 weeks), 0.0116 (6 weeks met); **P = 0.0005 m + p and 0.0015 met; ***P < 0.0001 by one-way ANOVA relative to MI vehicle. (E and F) Measures of (E) HW and (F) LW normalized to TL 6 weeks after MI or sham. *P = 0.0001 (HW), 0.0246 (LW); **P < 0.0001 relative to sham and tP = 0.0349; ttP = 0.0045 parox and 0.0077 m + p relative to MI vehicle by one-way ANOVA. n = 4 (met, m + p sham), 13 to 18 all other groups.

  • Fig. 8. Paroxetine decreases molecular markers of HF in post-MI mice.

    Analysis of WT murine hearts treated with vehicle, fluoxetine (fluox), paroxetine (parox), metoprolol (met), or metoprolol and paroxetine (m + p) at 6 weeks after MI compared to sham mice treated with vehicle or parox. (A) Quantification of GRK2 protein expression normalized to GAPDH from Western blots. *P = 0.0073; ***P = 0.0002 and 0.0004 by one-way ANOVA compared to sham values. n = 9 to 17 hearts per group from seven Western blots. (C to D) Quantification of RT-PCR data showing fold change in (B) ANF *P < 0.0001 except parox = 0.0008 and tP = 0.0145 parox and 0.0006 m + p; (C) BNP *P = 0.0458, **P < 0.0001 except met 0.0004, tP = 0.0223; and (D) βMHC mRNA expression in *P = 0.0052, **P < 0.0001; tP = 0.0383. All * relative to sham vehicle and t versus post-MI vehicle by one-way ANOVA. n = 6 to 14 per group.

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/7/277/277ra31/DC1

    Detailed Methods

    Fig. S1. Paroxetine restores βAR mRNA expression.

    Fig. S2. Paroxetine enhances myocyte contraction in response to ISO in control, but not in βARKct transgenic myocytes.

    Fig. S3. Paroxetine reduces LV dimension despite elevated GRK2 levels.

    Fig. S4. Paroxetine’s beneficial effect in post-MI HF is maintained after termination of treatment.

    Table S1. Reduction of LV dimension by paroxetine is not additive with GRK2 inhibition by βARKct.

    Source Data (Excel file)

  • Supplementary Material for:

    Paroxetine-mediated GRK2 inhibition reverses cardiac dysfunction and remodeling after myocardial infarction

    Sarah M. Schumacher, Erhe Gao, Weizhong Zhu, Xiongwen Chen, J. Kurt Chuprun, Arthur M. Feldman, John J. G. Tesmer, Walter J. Koch*

    *Corresponding author. E-mail: walter.koch@temple.edu

    Published 4 March 2015, Sci. Transl. Med. 7, 277ra31 (2015)
    DOI: 10.1126/scitranslmed.aaa0154

    This PDF file includes:

    • Detailed Methods
    • Fig. S1. Paroxetine restores βAR mRNA expression.
    • Fig. S2. Paroxetine enhances myocyte contraction in response to ISO in control, but not in βARKct transgenic myocytes.
    • Fig. S3. Paroxetine reduces LV dimension despite elevated GRK2 levels.
    • Fig. S4. Paroxetine’s beneficial effect in post-MI HF is maintained after termination of treatment.
    • Table S1. Reduction of LV dimension by paroxetine is not additive with GRK2 inhibition by βARKct.

    [Download PDF]

    Other Supplementary Material for this manuscript includes the following:

    • Source Data (Excel file)

    [Download Source Data]

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