The α2-adrenergic receptor pathway modulating depression influences the risk of arterial thrombosis associated with BDNFVal66Met polymorphism

Sandrini, Leonardo; Amadio, Patrizia; Ieraci, Alessandro; Malara, Alessandro; Werba, José Pablo; Soprano, Paolo M.; Balduini, Alessandra; Zara, M; Bonomi, Alice; Veglia, Fabrizio; Colombo, Gualtiero I.; Popoli, Maurizio; Lee, Francis S.; Tremoli, Elena; Barbieri, Silvia Stella

doi:10.1016/j.biopha.2021.112557

Cited by 4 publications

(4 citation statements)

References 59 publications

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“…To 40 µL of sample, pre-incubated at 37 °C in temperature bath for 1 min, were added 40 µL of platelet-poor plasma (PPP) and 40 µL of 15 mM CaCl 2 . Recalcification times have been converted to arbitrary units of tissue factor (TF) by using a calibration curve of thromboplastin extracted from human placenta (CSL Behring, Milan, Italy) [ 23 ].…”

Section: Methodsmentioning

confidence: 99%

Prenylcysteine Oxidase 1 (PCYOX1), a New Player in Thrombosis

Banfi

Amadio

Zara

et al. 2022

IJMS

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Prenylcysteine Oxidase 1 (PCYOX1) is an enzyme involved in the degradation of prenylated proteins. It is expressed in different tissues including vascular and blood cells. We recently showed that the secretome from Pcyox1-silenced cells reduced platelet adhesion both to fibrinogen and endothelial cells, suggesting a potential contribution of PCYOX1 into thrombus formation. Here, we show that in vivo thrombus formation after FeCl3 injury of the carotid artery was delayed in Pcyox1−/− mice, which were also protected from collagen/epinephrine induced thromboembolism. The Pcyox1−/− mice displayed normal blood cells count, vascular procoagulant activity and plasma fibrinogen levels. Deletion of Pcyox1 reduced the platelet/leukocyte aggregates in whole blood, as well as the platelet aggregation, the alpha granules release, and the αIIbβ3 integrin activation in platelet-rich plasma, in response to adenosine diphosphate (ADP) or thrombin receptor agonist peptide (TRAP). Washed platelets from the Pcyox1−/− and WT animals showed similar phosphorylation pathway activation, adhesion ability and aggregation. The presence of Pcyox1−/− plasma impaired agonist-induced WT platelet aggregation. Our findings show that the absence of PCYOX1 results in platelet hypo-reactivity and impaired arterial thrombosis, and indicates that PCYOX1 could be a novel target for antithrombotic drugs.

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Section: Methodsmentioning

confidence: 99%

Prenylcysteine Oxidase 1 (PCYOX1), a New Player in Thrombosis

Banfi

Amadio

Zara

et al. 2022

IJMS

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“…This dimorphism may involve epigenetic (201) and inflammatory (203) mechanisms. Despite a focus on BDNF in CNS responses and affective outcomes, recent evidence implicates BDNF signalling in thrombosis and CAD (204,205).…”

Section: Neurotrophin Signalling and Neurogenesismentioning

confidence: 99%

“…Animal models similarly evidence increased thrombosis in response to chronic stress (641,642). Increases in thrombopoiesis and platelet activity with stress involve both glucocorticoid and sympathetic influences (and associated inflammatory/ROS responses), together with potential roles for serotonin (643) and brain-derived neurotrophic factor (BDNF) signalling (204,644). The sympathoadrenal activation with chronic forms of stress primarily enhances coagulation, while fibrinolysis may be additionally influenced by acute stressors (322,645,646).…”

Section: Stress Is Pro-thromboticmentioning

confidence: 99%

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The sex-dependent response to psychosocial stress and ischaemic heart disease

Helman

Headrick

Stapelberg

et al. 2023

Front. Cardiovasc. Med.

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Stress is an important risk factor for modern chronic diseases, with distinct influences in males and females. The sex specificity of the mammalian stress response contributes to the sex-dependent development and impacts of coronary artery disease (CAD). Compared to men, women appear to have greater susceptibility to chronic forms of psychosocial stress, extending beyond an increased incidence of mood disorders to include a 2- to 4-fold higher risk of stress-dependent myocardial infarction in women, and up to 10-fold higher risk of Takotsubo syndrome—a stress-dependent coronary-myocardial disorder most prevalent in post-menopausal women. Sex differences arise at all levels of the stress response: from initial perception of stress to behavioural, cognitive, and affective responses and longer-term disease outcomes. These fundamental differences involve interactions between chromosomal and gonadal determinants, (mal)adaptive epigenetic modulation across the lifespan (particularly in early life), and the extrinsic influences of socio-cultural, economic, and environmental factors. Pre-clinical investigations of biological mechanisms support distinct early life programming and a heightened corticolimbic-noradrenaline-neuroinflammatory reactivity in females vs. males, among implicated determinants of the chronic stress response. Unravelling the intrinsic molecular, cellular and systems biological basis of these differences, and their interactions with external lifestyle/socio-cultural determinants, can guide preventative and therapeutic strategies to better target coronary heart disease in a tailored sex-specific manner.

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