title: Metformin reduces hyper-reactivity of platelets from patients with polycystic ovary syndrome by improving mitochondrial integrity.
abstract: 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 AMPKα1-dependent mechanism. In conclusion, the improvement of mitochondrial integrity and platelet reactivity may contribute to the beneficial effects of metformin on cardiovascular disease.
authors.affiliation: Voahanginirina Randriamboavonjy PhD, Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe-University, Theodor-Stern-Kai 7, D-60596 Frankfurt am Main, Germany, Tel.: +49 69 6301 6973, Fax: +49 69 6301 86880, Email: voahangy@vrc.uni-frankfurt.de.
authors.forename: Voahanginirina
authors.initials: V
authors.lastname: Randriamboavonjy
authors.forename: W Alexander
authors.initials: WA
authors.lastname: Mann
authors.forename: Amro
authors.initials: A
authors.lastname: Elgheznawy
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Popp
authors.forename: Paul
authors.initials: P
authors.lastname: Rogowski
authors.forename: Imke
authors.initials: I
authors.lastname: Dornauf
authors.forename: Stefan
authors.initials: S
authors.lastname: Dröse
authors.forename: Ingrid
authors.initials: I
authors.lastname: Fleming
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000097:blood / Q000235:genetics; D000328:Adult; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D016022:Case-Control Studies; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D034281:Dynamins; D004789:Enzyme Activation; D005260:Female; D020558:GTP Phosphohydrolases / Q000097:blood; D006801:Humans; D007333:Insulin Resistance; D008687:Metformin / Q000627:therapeutic use*; D008869:Microtubule-Associated Proteins / Q000097:blood; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D063154:Mitochondrial Dynamics / Q000187:drug effects; D024101:Mitochondrial Proteins / Q000097:blood; D053142:Mitochondrial Size / Q000187:drug effects; D010766:Phosphorylation; D015539:Platelet Activation / Q000187:drug effects*; D011085:Polycystic Ovary Syndrome / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D016896:Treatment Outcome
chemical_list: D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D008687:Metformin; C526181:PRKAA2 protein, human; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins
keywords: AMP-activated protein kinase; Metformin; dynamin-related protein 1; platelets; polycystic ovary syndrome