Role of mitochondria in atypical antipsychotics induced cardiovascular disorders
| Autor: | Patel, Gaurangkumar, Yildiz, Ramazan, García-Villalón, Angel Luís, Granado, Miriam, Monsalve, María |
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| Rok vydání: | 2019 |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| Popis: | Resumen del trabajo presentado al 42nd Congress of the Spanish Society of Biochemistry and Molecular Biology (SEBBM), celebrado en Madrid del 16 al 19 de julio de 2019. Schizophrenic patients require life-long treatment with atypical antipsychotics, also called as second generation antipsychotics (SGAs), like Olanzapine (Ola) being the most common. Long-term use of SGAs administration is associated with secondary metabolic effects like weight gain, dyslipidemia, and hyperglycemia which are considered as major risk factors for cardiovascular diseases (CVDs). However, the mechanisms involved have not been elucidated. Taking into account the central role played by mitochondrial dysfunction in the development of CVDs, we aimed to elucidate the role played by the possible interference of Olanzapine (Ola) and Aripiprazole (Ari) with mitochondrial function in CVDs. To that end, we used PGC-1a deficient (KO) mice as a model system of systemic mitochondrial dysfunction. We have compared the effects of subacute (ip, 28 days) and chronic (diet, 6 months) administration of Ari and Ola (5 mg/kg) on vascular reactivity of aortic rings from PGC-1a WT and KO mice tested ex-vivo. The effects of the treatment on the systemic use of oxygen was determined at 1 month, 3 months and 6 months of treatment using indirect calorimetry. We have found that Ari has more potent effect of than Ola, while both inhibited OCR in a PGC-1a dependent manner, supporting the hypothesis of induced mitochondrial dysfunction in treated mice. Vascular reactivity analysis showed that Ari enhanced the vascular constriction response to angiotensin II (Ang II) and endothelin 1 (ET1) and altered the dose response curve during relaxation to acetylcholine (Ach), whereas while Ola increased the response to norepinephrine (NE) at 1 and 6 months in WT mice. These effects were associated with corresponding changes in the gene expression pattern of the Ang II receptor AT1-R and the ET1 receptor ETA-R. These changes indicated a higher vascular toxicity of Ari that was dependent on mitochondrial function and affected in particular the response to Ang II and ET1 leading to hyper-reactivity. In sum, both Ari and Ola administration in mice reduce oxidative metabolism with Ari treatment being more potent. The observation that these changes do not occur in PGC-1a KO mice support the notion that they are dependent on the inhibition of oxidative metabolism. |
| Databáze: | OpenAIRE |
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