Abstract
Pulmonary arterial hypertension (PAH) is a devastating disease that is precipitated by hypertrophic pulmonary vascular remodeling of distal arterioles to increase pulmonary artery pressure and pulmonary vascular resistance in the absence of left heart, lung parenchymal, or thromboembolic disease. Despite available medical therapy, pulmonary artery remodeling and its attendant hemodynamic consequences result in right ventricular dysfunction, failure, and early death. To limit morbidity and mortality, attention has focused on identifying the cellular and molecular mechanisms underlying aberrant pulmonary artery remodeling to identify pathways for intervention. While there is a well-recognized heritable genetic component to PAH, there is also evidence of other genetic perturbations, including pulmonary vascular cell DNA damage, activation of the DNA damage response, and variations in microRNA expression. These findings likely contribute, in part, to dysregulation of proliferation and apoptosis signaling pathways akin to what is observed in cancer; changes in cellular metabolism, metabolic flux, and mitochondrial function; and endothelial-to-mesenchymal transition as key signaling pathways that promote pulmonary vascular remodeling. This review will highlight recent advances in the field with an emphasis on the aforementioned molecular mechanisms as contributors to the pulmonary vascular disease pathophenotype.
Highlights
Pulmonary hypertension, defined as a mean pulmonary artery pressure ě25 mmHg, may be a primary disorder or occur secondary to cardiopulmonary disease or a consequence of other clinical disorders [1]
We will summarize some of the recent advances in the field with a focus on genetic and epigenetic phenomenon, metabolism and mitochondrial function, mineral and essential element handling, and endothelial-to-mesenchymal transition (EndoMT) as key regulatory pathways involved in pulmonary vascular remodeling and Pulmonary arterial hypertension (PAH)
The diverse cellular and molecular pathways that are operative in PAH converge to generate a pathophenotype that is characterized by distal pulmonary artery hypertrophic remodeling that increases pulmonary vascular resistance and pulmonary artery pressure
Summary
Pulmonary hypertension, defined as a mean pulmonary artery pressure ě25 mmHg, may be a primary disorder or occur secondary to cardiopulmonary disease or a consequence of other clinical disorders [1]. Whole exome sequencing found rare genetic variants associated with PAH [8] Using this methodology, variants in the genes for caveolin (CAV1), which regulates SMAD 2/3 phosphorylation, the potassium channel, subfamily K, member 3 (KCNK3), which is expressed by pulmonary artery smooth muscle cells and related to proliferation, and the eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4), which has been implicated in pulmonary vaso-occlusive disease in an autosomal recessive manner [9,10,11]. Mutations in KCNA5, the potassium channel voltage gated shaker-related subfamily A, member 5, which is involved in maintaining the pulmonary artery smooth muscle cell contractile state, have been identified as a “second-hit” in patients with BMPR2 mutations [13] When present, this mutation enhances the effects of the BMPR2 mutation to cause early onset and severe PAH [8]. While these mutations and variants have been linked to PAH by affecting pathways relevant for pulmonary vascular homeostasis, other genetic and epigenetic mechanisms such as the presence of DNA damage, activation of the DNA damage response, and microRNAs (miR) influence gene expression and downstream signaling pathways
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