sodium-ethylxanthate and Hypertension--Pulmonary

Pulmonary arterial hypertension (PAH) is up to threefold more prevalent in women than men. Female mice overexpressing the serotonin transporter (SERT; SERT+ mice) exhibit PAH and exaggerated hypoxia-induced PAH, whereas male SERT+ mice remain unaffected. To further investigate these sex differences, microarray analysis was performed in the pulmonary arteries of normoxic and chronically hypoxic female and male SERT+ mice. Quantitative RT-PCR analysis was employed for validation of the microarray data. In relevant groups, immunoblotting was performed for genes of interest (CEBPβ, CYP1B1, and FOS). To translate clinical relevance to our findings, CEBPβ, CYP1B1, and FOS mRNA and protein expression was assessed in pulmonary artery smooth muscle cells (PASMCs) derived from idiopathic PAH (IPAH) patients and controls. In female SERT+ mice, multiple pathways with relevance to PAH were altered. This was also observed in chronically hypoxic female SERT+ mice. We selected 10 genes of interest for qRT-PCR analysis (FOS, CEBPβ, CYP1B1, MYL3, HAMP2, LTF, PLN, NPPA, UCP1, and C1S), and 100% concordance was reported. Protein expression of three selected genes, CEBPβ, CYP1B1, FOS, was also upregulated in female SERT+ mice. Serotonin and 17β-estradiol increased CEBPβ, CYP1B1, and FOS protein expression in PASMCs. In addition, CEBPβ, CYP1B1, and FOS mRNA and protein expression was also increased in PASMCs derived from IPAH patients. Here, we have identified a number of genes that may predispose female SERT+ mice to PAH, and these findings may also be relevant to human PAH.

Topics: Animals; Animals, Genetically Modified; Aryl Hydrocarbon Hydroxylases; CCAAT-Enhancer-Binding Protein-beta; Cell Culture Techniques; Chemical and Drug Induced Liver Injury, Chronic; Cytochrome P-450 CYP1B1; Estrogens; Familial Primary Pulmonary Hypertension; Female; Gene Expression; Gene Expression Profiling; Humans; Hypertension, Pulmonary; Hypoxia; Male; Mice; Microarray Analysis; Myocytes, Smooth Muscle; Proto-Oncogene Proteins c-fes; Pulmonary Artery; Serotonin Plasma Membrane Transport Proteins; Sex

To determine whether impaired reactivity to dilatory agonists could contribute to pulmonary hypertension, and whether there are gender differences in pulmonary vasodilator reactivity.. Pulmonary arterial rings from monocrotaline (MCT)-induced pulmonary hypertensive and control rats were isolated. At the peaks of submaximal contractions to norepinephrine (NE) or endothelin (ET-1), rings were exposed to 5 x 10(-6) M acetylcholine (ACh) or 9 x 10(-9) M adrenomedullin (ADM) or 1.3 x 10(-8) M calcitonin gene-related peptide (CGRP).. Relaxation to ACh, ADM, and CGRP was endothelium-dependent. Hypertensive pulmonary arterial rings relaxed less to ACh and CGRP than controls in both genders. Female pulmonary hypertensive muscle was more rather than less reactive to ADM compared with controls. ADM-induced relaxation of NE contractions was 2.4 times greater in female compared with male control rings and 5.5 times greater in female compared with male hypertensive preparations. Gender differences in relaxation responses were similar for CGRP. MCT-treated female arterial rings relaxed more than did MCT-treated male arterial muscle in response to ACh. No difference in ACh relaxation was found between genders for controls.. Pulmonary arterial relaxation to endothelium-dependent vasodilators is impaired in MCT-induced pulmonary hypertension with the exception of ADM in females. Vasodilators may be more effective in reducing pulmonary hypertension in females than in males.

Topics: Acetylcholine; Adrenomedullin; Animals; Calcitonin Gene-Related Peptide; Endothelins; Female; Hypertension, Pulmonary; Male; Monocrotaline; Norepinephrine; Peptides; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Sex; Vasodilation; Vasodilator Agents