Gender, Sex Hormones and Pulmonary Hypertension

Austin, Eric D.; Lahm, Tim; West, James; Tofovic, Stevan P.; Johansen, Anne Katrine; MacLean, Margaret R.; Kheirallah, Khalid; Oka, Masahiko

doi:10.4103/2045-8932.114756

Cited by 86 publications

(88 citation statements)

References 232 publications

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“…[45][46][47] Male but not female mice had increased expression of the miR-199/214 axis in the lung and RV in SU 4516 hypoxia-induced PAH (Figs. 2C, 2D, 3C, 3D).…”

Section: Discussionmentioning

confidence: 99%

Regulation and Function of miR‐214 in Pulmonary Arterial Hypertension

et al. 2016

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Dysregulation of microRNAs (miRNAs) can contribute to the etiology of diseases, including pulmonary arterial hypertension (PAH). Here we investigated a potential role for the miR-214 stem loop miRNA and the closely linked miR-199a miRNAs in PAH. All 4 miRNAs were upregulated in the lung and right ventricle (RV) in mice and rats exposed to the Sugen (SU) 5416 hypoxia model of PAH. Further, expression of the miRNAs was increased in pulmonary artery smooth muscle cells exposed to transforming growth factor β1 but not BMP4. We then examined miR-214 −/− mice exposed to the SU 5416 hypoxia model of PAH or normoxic conditions and littermate controls. There were no changes in RV systolic pressure or remodeling observed between the miR-214 −/− and wild-type hypoxic groups. However, we observed a significant increase in RV hypertrophy (RVH) in hypoxic miR-214 −/− male mice compared with controls. Further, we identified that the validated miR-214 target phosphatase and tensin homolog was upregulated in miR-214 −/− mice. Thus, miR-214 stem loop loss leads to elevated RVH and may contribute to the heart failure associated with PAH. Pulmonary arterial hypertension (PAH) is a disease characterized by narrowing of the small pulmonary arteries, leading to vascular remodeling, an elevation in pulmonary artery pressure, right ventricular hypertrophy (RVH), and heart failure. 1 Current therapies for PAH aim to reverse the endothelial dysfunction and vasoconstriction observed. 2 However, despite these therapies, PAH mortality rates remain high, and the 3-year survival of patients is only 54.9%. 3 Changes in the pulmonary vasculature are the primary cause of PAH; however, right ventricle (RV) function is a major determinant of the severity of symptoms and prognosis of pulmonary hypertension. Many therapies in development for PAH are focused on targeting the RV since heart failure is the ultimate cause of mortality in PAH. 4 PAH is predominant in females, with female ∶ male ratios of 1.4-4.1 ∶ 1. 5 Sexual dimorphism has also been observed in RV failure. Female PAH patients exhibit improved RV ejection fraction and survival compared with men. 6 This could be due at least in part to the protective effect of estrogen on RV function. 7,8 MicroRNAs (miRNAs) are involved in multiple cellular responses during normal development and disease; they act as posttranscriptional regulators to fine-tune protein synthesis. Evidence has emerged for a key role for miRNA in regulation of the cellular processes involved in PAH. We previously demonstrated that a range of miRNAs are dysregulated in rats exposed to models of PAH. 9 Later studies have shown that miR-21, the miR-143/145 cluster, miR-27a, the miR-17-92 cluster, miR-124, miR-150, miR-138, miR-190, miR-204, miR-206, miR-210, and miR-328 play a role in the development of PAH. 10 Multiple miRNAs could potentially be targeted in concert as therapeutics in PAH. 11 MicroRNA miR-214 is transcribed as a bicistronic primary transcript, which is processed to generate 4 separate mature miRNAs...

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“…[45][46][47] Male but not female mice had increased expression of the miR-199/214 axis in the lung and RV in SU 4516 hypoxia-induced PAH (Figs. 2C, 2D, 3C, 3D).…”

Section: Discussionmentioning

confidence: 99%

Regulation and Function of miR‐214 in Pulmonary Arterial Hypertension

et al. 2016

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“…The idiopathic form of PAH (IPAH) has no identifiable etiology, affects mostly young women, and if treated has an average survival of 2-3 years from the time of diagnosis. 7,[11][12][13][14] Currently, therapies target pulmonary vasoconstriction, and our ability to manage PAH remains poor because of our limited knowledge of the disease pathogenesis. Multiple phenotypes (other than vasoconstriction), such as dysregulated pulmonary vascular cell proliferation and remodeling, increased angiogenesis, and inflammation, contribute to the PAH disease process.…”

Section: Introductionmentioning

confidence: 99%

Novel Methods in Pulmonary Hypertension Phenotyping in the Age of Precision Medicine (2015 Grover Conference Series)

et al. 2016

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Among pulmonary vascular diseases, pulmonary hypertension (PH) is the best studied and has been the focus of our work. The current classification of PH is based on a relatively simple combination of patient characteristics and hemodynamics. This leads to inherent limitations, including the inability to customize treatment and the lack of clarity from a more granular identification based on individual patient phenotypes. Accurate phenotyping of PH can be used in the clinic to select therapies and determine prognosis and in research to increase the homogeneity of study cohorts. Rapid advances in the mechanistic understanding of the disease, improved imaging methods, and innovative biomarkers now provide an opportunity to define novel PH phenotypes. We have recently shown that altered metabolism may affect nitric oxide levels and protein glycosylation, the peripheral circulation (which may provide insights into the response to therapy), and exhaled-breath analysis (which may be useful in disease evaluation). This review is based on a talk presented during the 2015 Grover Conference and highlights the relevant literature describing novel methods to phenotype pulmonary arterial hypertension patients by using approaches that involve the pulmonary and systemic (peripheral) vasculature. In particular, abnormalities in metabolism, the pulmonary and peripheral circulation, and exhaled breath in PH may help identify phenotypes that can be the basis for a precision-medicine approach to PH management. These approaches may also have a broader scope and may contribute to a better understanding of other diseases, such as asthma, diabetes, and cancer.

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“…In this regard, the 2-hydroxylation-catechol-O-methyltransferase pathway produces nonestrogenic, antiproliferative, antiangiogenic, and antiinflammatory metabolites (2-hydroxyestradiol and 2-methoxyestradiol), and these metabolites are protective in hypoxia-, monocrotaline-, sugene 1 hypoxia-, and bleomycin-induced PAH (2). In contrast, the 4-hydroxylation and 16-hydroxylation pathways produce 4-hydroxyestradiol and 16a-hydroxyestrone, which are estrogenic, very reactive, and exert significant mitogenic, angiogenic, and inflammatory actions (2,3,10).…”

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confidence: 99%

“…The apparent contradictions posed by the effects of female sex and estrogens in experimental PAH versus human PAH could be explained by the limitations of the experimental models used and the opposite roles estradiol may play in the pulmonary vasculature versus the right ventricle ( Figure 1C). Although the estrogen paradox remains unresolved, mounting evidence (both in patients with PAH and in novel rodent models of angioproliferative PAH) suggests that precursors and metabolites of sex steroids influence the development and progression of PAH and could account for the estrogen paradox (2,3).…”

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confidence: 99%

“…Since the first report that 2-methoxyestradiol (major nonestrogenic metabolite of estradiol) attenuates the development and progression of monocrotaline-induced PAH (9), it has become increasingly clear that estradiol precursors, estradiol per se, and estradiol metabolites can exhibit both detrimental and protective effects in PAH (2,3). In this regard, the 2-hydroxylation-catechol-O-methyltransferase pathway produces nonestrogenic, antiproliferative, antiangiogenic, and antiinflammatory metabolites (2-hydroxyestradiol and 2-methoxyestradiol), and these metabolites are protective in hypoxia-, monocrotaline-, sugene 1 hypoxia-, and bleomycin-induced PAH (2).…”

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confidence: 99%

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