ABC | Volume 112, Nº1, January 2019

Original Article Sex–Related Effects of Prenatal Stress on Region-Specific Expression of Monoamine Oxidase A and β Adrenergic Receptors in Rat Hearts Tanja Jevjdovic, 1 Tamara Dakic, 1 Sonja Kopanja, 2 Iva Lakic, 1 Predrag Vujovic, 1 Nebojsa Jasnic, 1 Jelena Djordjevic 1 Faculty of Biology - University of Belgrade, 1 Belgrado - Sérvia Department of Pediatrics and Adolescent Medicine - Medical University of Vienna, 2 Viena – Áustria Mailing Address: Tanja Jevjdovic • Studentski trg 16, 11000, Belgrade – Sérvia E-mail: tanja.jevdjovic@bio.bg.ac.rs, tanja.jevdjovic@gmail.com Manuscript received February 01, 2018, revised manuscript June 14, 2018, accepted July 23, 2018 DOI: 10.5935/abc.20190001 Abstract Background: Prenatal stress may increase risk of developing cardiovascular disorders in adulthood. The cardiotoxic effects of catecholamines are mediated via prolonged adrenergic receptor stimulation and increased oxidative stress upon their degradation by monoamine oxidase A (MAO-A). Objectives: We investigated long-term effects of prenatal stress on β (1, 2, 3) adrenergic receptors and MAO-A gene expression in the hearts of adult rat offspring. Methods: Pregnant rats were exposed to unpredictable mild stress during the third week of gestation. RNA was isolated from left ventricular apex and base of adult offspring. Quantitative PCR was used to measure gene expression in collected ventricular tissue samples. The level of significance was set to p < 0.05. Results: β 3 adrenergic receptor mRNAwas undetectable in rat left ventricle. β 1 adrenergic receptor was the predominantly expressed subtype at the apical and basal left ventricular myocardium in the control females. Male offspring from unstressed mothers displayed higher apical cardiac β 1 than β 2 adrenergic receptor mRNA levels. However, β 1 and β 2 adrenergic receptor mRNAs were similarly expressed at the ventricular basal myocardium in males. Unlike males, prenatally stressed females exhibited decreased β 1 adrenergic receptor mRNA expression at the apical myocardium. Prenatal stress did not affect cardiac MAO-A gene expression. Conclusions: Collectively, our results show that prenatal stress may have exerted region- and sex-specific β 1 and β 2 adrenergic receptor expression patterns within the left ventricle. (Arq Bras Cardiol. 2019; 112(1):67-75) Keywords: Pregnancy; Stress, Physiological; Oxidative Stress; Heart; Catecholamines; Rats; Sex; Female; Cardiotoxicity; Adrenergic beta1 beta2 Receptor Antagonists. Introduction Emerging data from epidemiological and experimental studies have pointed out that disturbed intrauterine environment is related to the increased risk of developing pathologies later in life. Increased susceptibility to adult hypertension has been observed in offspring prenatally exposed to unbalanced maternal nutrition, 1-3 synthetic glucocorticoids, 4 or maternal stress. 5 It has long been recognized that exposure to prenatal stress results in enhanced hypothalamo-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) activity in adulthood. 6,7 The hallmark of cardiovascular disorders is dysregulated SNS activity. Hence, it is not surprising that the key pharmaceutical targets in the management of these disorders are mostly modulators of adrenergic receptor activity. Cardiotoxic effects of catecholamines are mainly mediated via persistent or acute over-stimulation of β adrenergic receptors (ADRB). 8 A healthy human heart expresses three ADRB subtypes, with ADRB1 being the most and ADRB3 the least abundant. 9,10 Downregulation in the ADRB1 subpopulation is one of the molecular features of cardiac pathologies, such as human heart failure. 9,11 Furthermore, animal transgenic studies demonstrated that early effects of ADRB2 overexpression led to increased cardiac contractility. 12 However, later in life these transgenic animals developed ventricular dysfunction. 13 Furthermore, another myocardial pathological condition triggered by high circulating catecholamines is defined by a region-specific, mostly apical, contractile dysfunction within the left ventricle. 14 Additionally, cardiotoxicity may result from the production of reactive oxidative species (ROS) upon catecholamine degradation by monoamine oxidase A (MAO-A) in the heart. 15 Cardiac MAO-A expression and activity is increased in different animal models of heart failure 16-18 and aging. 19 Epidemiological studies showed that female and male patients suffering from cardiovascular disease exhibit differential responsiveness to diverse recommended treatments, 20,21 emphasizing the necessity to include both sexes in cardiovascular research. 67