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Flow-activated transcription factor Krüppel-like factor 2 (KLF2) signaling is compromised in pulmonary arterial hypertension (PAH). We aimed to identify KLF2-induced endothelium-protective exosomal microRNAs of potential therapeutic significance.Eight exosomal microRNAs elevated by KLF2 but reduced in PAH were transfected into human pulmonary artery endothelial cells. Of these, only miR-181a-5p and miR-324-5p had anti-apoptotic, anti-inflammatory and anti-proliferative effect on endothelial cells and reduced proliferation of vascular smooth muscle cells in vitro. RNA sequencing of miRNA-transfected HPAECs revealed reduced expression of multiple genes implicated in vascular remodelling, including ETS-1, NOTCH4, ACTA2, TNF-α, IL-1, MMP10, MAPK and NFATC2. KLF2, miR-181a-5p and miR-324-5p were reduced, while their target genes were elevated in blood-derived endothelial colony forming cells and lung tissues from idiopathic and heritable PAH patients with disabling KLF2 mutation and Sugen/hypoxia mice. Supplementation of miR-181a-5p and miR-324-5p or silencing of their target genes attenuated proliferative and angiogenic responses in endothelial cells from idiopathic PAH and prevented development of pulmonary hypertension in Sugen/hypoxia mice.This study highlights potential therapeutic role of KLF2-induced exosomal microRNAs in PAH.

The 2015 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension (PH) are also valid for Germany. While the guidelines contain detailed recommendations regarding clinical aspects of pulmonary arterial hypertension (PAH) and other forms of PH, they contain only a relatively short paragraph on novel findings on the pathobiology, pathology, and genetics. However, these are of great importance for our understanding of this complex disease both from a clinical and scientific point of view, and they are essential for the development of novel treatment strategies. To this end, a number of current data are relevant, prompting a detailed commentary to the guidelines, and the consideration of new scientific data. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to the pathobiology, pathology and genetics of PH. This article summarizes the results and recommendations of this working group.

Pulmonary arterial hypertension (PAH) can be found in patients suffering from a loss-of-function mutation of the gene encoding for the activin receptor-like kinase 1 (ALK-1), a bone morphogenetic protein (BMP) type 1 receptor. Interestingly, ALK-1 mutations also lead to hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant disease characterized by arteriovenous malformations (AVMs) leading to potentially life-threatening bleeding complications such as epistaxis. Current therapeutic options for both diseases are limited and often only temporary or accompanied by severe side effects. Here, we report of a patient with a mutation of the ALK-1 gene suffering from both HHT and PAH. Recently, it was shown that tacrolimus increased ALK-1 signaling and had beneficial effects in selected end-stage PAH patients. We thus hypothesized that treatment with tacrolimus may prevent disease progression in this patient. Surprisingly, treatment with low-dose tacrolimus dramatically improved his HHT-associated epistaxis but did not attenuate progression of PAH. CA extern