Cardiac soluble guanylate cyclase protects against the cardiac dysfunction induced by chronic doxorubicin treatment in mice
BMC Pharmacology and Toxicology volume 16, Article number: A96 (2015)
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).
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).
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.
Stefan P Janssens and Emmanuel S Buys contributed equally to this work.
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Vandenwijngaert, S., Swinnen, M., Gillijns, H. et al. Cardiac soluble guanylate cyclase protects against the cardiac dysfunction induced by chronic doxorubicin treatment in mice. BMC Pharmacol Toxicol 16 (Suppl 1), A96 (2015). https://doi.org/10.1186/2050-6511-16-S1-A96