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

Voahanginirina Randriamboavonjy; W. Alexander Mann; Amro Elgheznawy; Rüdiger Popp; Paul Rogowski; Imke Dornauf; Stefan Dröse; Ingrid Fleming

doi:10.1160/TH14-09-0797

Thrombosis and Haemostasis, Inhaltsverzeichnis

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^#

¹Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany

,

W. Alexander Mann^#

²Endokrinologikum Frankfurt, Frankfurt am Main, Germany

,

Amro Elgheznawy

¹Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany

,

Rüdiger Popp

¹Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany

,

Paul Rogowski

¹Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany

²Endokrinologikum Frankfurt, Frankfurt am Main, Germany

,

Imke Dornauf

²Endokrinologikum Frankfurt, Frankfurt am Main, Germany

,

Stefan Dröse

³Department of Anesthesiology, Intensive-Care Medicine and Pain Therapy, Goethe-University Hospital Frankfurt, Frankfurt am Main, Germany

,

Ingrid Fleming

¹Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany

› Institutsangaben

Abstract

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

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Referenzen

References
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