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01.12.2018 | Research | Ausgabe 1/2018 Open Access

Journal of Translational Medicine 1/2018

Large-scale in silico identification of drugs exerting sex-specific effects in the heart

Zeitschrift:
Journal of Translational Medicine > Ausgabe 1/2018
Autoren:
Changting Cui, Chuanbo Huang, Kejia Liu, Guoheng Xu, Jichun Yang, Yong Zhou, Yingmei Feng, Georgios Kararigas, Bin Geng, Qinghua Cui
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s12967-018-1612-6) contains supplementary material, which is available to authorized users.
Changting Cui and Chuanbo Huang contributed equally to this work

Abstract

Background

Major differences exist between men and women in both physiology and pathophysiology. Dissecting the underlying processes and contributing mechanisms of sex differences in health and disease represents a crucial step towards precision medicine. Considering the significant differences between men and women in the response to pharmacotherapies, our aim was to develop an in silico model able to predict sex-specific drug responses in a large-scale.

Methods

For this purpose, we focused on cardiovascular effects because of their high morbidity and mortality. Our model predicted several drugs (including acebutolol and tacrine) with significant differences in the heart between men and women. To validate the sex-specific drug responses identified by our model, acebutolol was selected to lower blood pressure in spontaneous hypertensive rats (SHR), tacrine was used to assess cardiac injury in mice and metformin as control for a non-sex-specific response.

Results

As our model predicted, acebutolol exhibited a stronger decrease in heart rate and blood pressure in female than male SHRs. Tacrine lowered heart rate in male but not in female mice, induced higher plasma cTNI level and increased cardiac superoxide (DHE staining) generation in female than male mice, indicating stronger cardiac toxicity in female than male mice. To validate our model in humans, we employed two Chinese cohorts, which showed that among patients taking a beta-receptor blocker (metoprolol), women reached significantly lower diastolic blood pressure than men.

Conclusions

We conclude that our in silico model could be translated into clinical practice to predict sex-specific drug responses, thereby contributing towards a more appropriate medical care for both men and women.
Zusatzmaterial
Additional file 1. List of female-biased genes and male biased genes on human heart.
Additional file 2. List of predicted sex-responsive drugs on human heart.
Additional file 3: Figure S1. The mean DHE fluorescence density analysis from DHE staining.
Additional file 4: Figure S2. The chemical structures of acebutolol and metoprolol. The red circle showed the difference of two drugs in chemical groups.
Additional file 5: Figure S3. The changes of hemodynamic changes after administration of acebutolol combination with hydrochlorothiazide. The systolic blood pressure (a), diastolic blood pressure (b), the minus of heart rate (c) and heart rate (d) changes after taken acebutolol combination and hydrochlorothiazide for 12 weeks from study of Sutandar.
Literatur
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