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.

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“…In addition, we evaluated the effect of metformin on thrombus (metformin: 200 mg/kg twice a day for 7 days)2526, particularly on diabetic rat thrombus, since metformin is an antidiabetic drug6. Metformin showed similar effects on preventing arterial (Fig.…”

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New insights into the genic and metabolic characteristics of induced pluripotent stem cells from polycystic ovary syndrome women

“…These phenomena indicated that the integrity of mitochondria was affected in PCOS patient-derived iPSCs, leading to mitochondrial dysfunction. The decrease in mitochondrial function may then stimulate more mitochondrial biogenesis by a compensatory effect [ 18 ].…”

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“…Moreover, studies show that metformin slightly reduces body mass and arterial blood pressure in overweight and obese people [107][108][109]. It may also improve lipid profile and balance between profibrinolytic and anti-thrombotic factors [5,110]. However, recently the results of research showing potential anti-neoplastic and anti-ageing effects of metformin are of particular interest to scientists and clinicians [36,37,111,112].…”