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  • Meeting abstract
  • Open Access

Cardiac soluble guanylate cyclase protects against the cardiac dysfunction induced by chronic doxorubicin treatment in mice

  • 1Email author,
  • 2,
  • 2,
  • 2,
  • 1,
  • 1,
  • 1,
  • 2, 3,
  • 4,
  • 1,
  • 1,
  • 2 and
  • 1
Contributed equally
BMC Pharmacology and Toxicology201516 (Suppl 1) :A96

https://doi.org/10.1186/2050-6511-16-S1-A96

  • Published:

Keywords

  • Leave Ventricular Dysfunction
  • Leave Ventricular Systolic Dysfunction
  • Soluble Guanylate Cyclase
  • Riociguat
  • cGMP Synthesis

Background

The use of doxorubicin (DOX), a potent chemotherapeutic agent, is limited by cardiotoxicity, leading to congestive heart failure in up to 5% of DOX-treated patients. Dysfunctional cyclic guanosine 3’, 5’-monophosphate (cGMP) signaling has been implicated in various cardiovascular diseases, including cardiotoxicity associated with DOX administration. We tested the hypothesis that cGMP generated by soluble guanylate cyclase (sGC), the target for clinically available pharmacological agents that enhance cGMP levels (e.g. riociguat), protects against DOX-induced cardiomyopathy.

Methods and results

Nitric oxide (NO)-stimulated sGC enzyme activity was lower in myocardial tissue extracts from wild-type (WT) mice exposed to DOX (20 mg/kg, IP, 24h), than from vehicle-treated WT mice (20.4±2.1 vs. 25.7±1.4 pmol cGMP/mg protein/min, respectively, n=10 for both, P<0.05). To investigate whether decreased cardiac cGMP synthesis by sGC contributes to DOX-induced cardiotoxicity, we studied mice with a cardiomyocyte-specific deficiency in the α1-subunit of sGC (sGCα1-/-), obtained using a Cre-lox conditional knockout strategy. At baseline, left ventricular (LV) dimensions and function, assessed via transthoracic echocardiography (TTE), were similar in sGCα1-/- and WT mice. After 12 weeks DOX (2 mg/kg/week, IP), TTE and invasive hemodynamic measurements revealed greater LV dysfunction and dilatation in sGCα1-/- than in WT mice (Table 1).
Table 1

DOX-induced LV dysfunction and remodeling after 12 weeks chronic treatment is greater in sGCα1-/- than WT mice:

Echocardiography

WT + saline (n=7)

sGCα1-/- + saline (n=6)

WT + DOX (n=12)

sGCα1-/- + DOX (n=11)

LVIDS (mm)

1.3±0.1

1.3±0.0

1.7±0.1†

2.0±0.1†*

LVIDD (mm)

3.0±0.0

3.0±0.0

3.2±0.1†

3.3±0.0†

FS (%)

57±1

57±1

48±2†

40±1†*

HR (bpm)

531±13

505±18

428±17†

426±18†

Hemodynamic measurements

WT + saline (n=6)

sGCα1-/- + saline (n=5)

WT + DOX (n=12)

sGCα1-/- + DOX (n=9)

ESV (μl)

19±1

19±1

26±3†

37±3†*

EDV (μl)

43±2

41±2

51±2†

58±2†*

EF (%)

60±2

58±3

55±4

42±3†*

dP/dtmax (mmHg/s)

13,499±1,433

11,995±601

13,503±678

10,386±875*

dP/dtmin (mmHg/s)

-12,053±1,809

-11,420±950

-13,531±846

-10,943±940¶

Tau (ms)

5.1±0.1

4.9±0.2

5.6±0.2†

6.3±0.3†¶

PRSW

83±9

84±6

70±9

49±7†¶

Ees (mmHg/μl)

6.3±1.2

7.3±1.4

4.0±0.8†

2.3±0.3†¶

EDPVR (mmHg/μl)

0.21±0.03

0.18±0.02

0.16±0.02

0.19±0.02

HR (bpm)

576±8

614±12

528±9†

530±14†*

LVIDS indicates left ventricular internal diameter at end-systole; LVIDD, left ventricular internal diameter at end-diastole; FS, fractional shortening; HR, heart rate; ESV, end-systolic volume; EDV, end-diastolic volume; EF, ejection fraction; dP/dtmax and dP/dtmin, maximum and minimum of the first derivative of LV pressure over time; Tau, time constant for isovolumic relaxation; PRSW, pre-load recruitable stroke work; Ees, end-systolic elastance; and EDPVR, end-diastolic pressure volume relationship. Values are presented as mean±SEM.

P<0.05 vs. saline,

* P<0.05 vs. WT + DOX, and

P≤0.10 vs. WT + DOX.

In a second mouse model, myocardial sGC activity was reduced by cardiomyocyte-specific expression of a dominant-negative sGCα1 mutant (DNsGCα1tg/+) in an inducible manner (Tet-Off). Withdrawing tetracycline from the diet resulted in a ~50% reduction of cardiac sGC activity (18.6±2.6 vs. 32.0±5.4 pmol cGMP/mg protein/min in 8 DNsGCα1tg/+and 8 WT mice, respectively, P<0.05). At baseline, LV dimensions and function were similar in DNsGCα1tg/+and WT mice. Chronic DOX treatment resulted in greater LV systolic dysfunction and dilatation in DNsGCα1tg/+ than in WT mice after 8 and 12 weeks (TTE, data not shown). Importantly, LV dysfunction observed in DNsGCα1tg/+exposed to DOX for 12 weeks could be attenuated by re-adding tetracycline to the diet [thereby suppressing expression of the dominant negative sGCα1 mutant and de-repressing endogenous sGC activity] after 8 weeks of DOX administration: fractional shortening improved significantly in DNsGCα1tg/+ mice by 16 weeks (28±1% at 8 weeks vs. 35±1% at 16 weeks, n=17 and 20, respectively, P <0.05).

Conclusions

Reduced myocardial sGC activity results in increased LV dysfunction and dilatation in DOX-treated mice. Pharmacological stimulation of sGC may represent a promising therapeutic approach to tackle DOX-associated cardiotoxicity.

Notes

Authors’ Affiliations

(1)
Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
(2)
Department of Cardiovascular Sciences, KU Leuven, Leuven, 3000, Belgium
(3)
Cardiovascular Center, OLV Hospital, Aalst, 9300, Belgium
(4)
Department of Biomedical Molecular Biology, Ghent University and Flanders Institute for Biotechnology, Ghent, 9000, Belgium

Copyright

© Vandenwijngaert et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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