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Thromb Haemost 2015; 114(03): 569-578
DOI: 10.1160/TH14-09-0797
Cellular Haemostasis and Platelets
Schattauer GmbH

Metformin reduces hyper-reactivity of platelets from patients with polycystic ovary syndrome by improving mitochondrial integrity

Voahanginirina Randriamboavonjy   #
1   Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany
,
W. Alexander Mann   #
2   Endokrinologikum Frankfurt, Frankfurt am Main, Germany
,
Amro Elgheznawy
1   Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany
,
Rüdiger Popp
1   Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany
,
Paul Rogowski
1   Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany
2   Endokrinologikum Frankfurt, Frankfurt am Main, Germany
,
Imke Dornauf
2   Endokrinologikum Frankfurt, Frankfurt am Main, Germany
,
Stefan Dröse
3   Department of Anesthesiology, Intensive-Care Medicine and Pain Therapy, Goethe-University Hospital Frankfurt, Frankfurt am Main, Germany
,
Ingrid Fleming
1   Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany
› Author Affiliations Financial support:This study was supported by the Deutsche Forschungsgemeinschaft, (SFB 815/A16 and A02; SFB 834/A5; Exzellenzcluster 147 “Cardio-Pulmonary System”) and the German Centre for Cardiovascular Research (DZHK) partner site RhineMain. AE was supported by a German Egyptian Research Long-term Scholarship funded by the Egyptian Ministry of Higher Education and Scientific Research and the German Academic Exchange Service.
Further Information

Publication History

Received: 25 September 2014

Accepted after major revision: 11 April 2015

Publication Date:
01 December 2017 (online)

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Summary

Polycystic ovary syndrome (PCOS) is associated with decreased fertility, insulin resistance and an increased risk of developing cardiovascular disease. Treating PCOS patients with metformin improves fertility and decreases cardiovascular complications. Given that platelet activation contributes to both infertility and cardiovascular disease development, we assessed platelet reactivity in PCOS patients and the consequences of metformin treatment. Compared to washed platelets from healthy donors, platelets from PCOS patients demonstrated enhanced reactivity and impaired activation of the AMP-activated kinase (AMPK). PCOS platelets also demonstrated enhanced expression of mitochondrial proteins such as the cytochrome c reductase, ATP synthase and the voltage-dependent anion channel-1. However, mitochondrial function was impaired as demonstrated by a decreased respiration rate. In parallel, the phosphorylation of dynamin-related protein-1 (Drp-1) on Ser616 was increased while that on Ser637 decreased. The latter changes were accompanied by decreased mitochondrial size. In insulin-resistant PCOS patients (HOMA-IR> 2) metformin treatment (1.7 g per day for 4 weeks to 6 months) improved insulin sensitivity, restored mitochondrial integrity and function and normalised platelet aggregation. Treatment was without effect in PCOS patients with HOMA-IR< 2. Moreover, treatment of megakaryocytes with metformin enhanced mitochondrial content and in the same cells metformin enhanced the phosphorylation of the Drp-1 on Ser637 via an AMPK[uni03B1]1-dependent mechanism. In conclusion, the improvement of mitochondrial integrity and platelet reactivity may contribute to the beneficial effects of metformin on cardiovascular disease.

Keywords

Metformin - polycystic ovary syndrome - platelets - dynamin-related protein 1 - AMP-activated protein kinase

# V. R. and W. A.M contributed equally.


 

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