Pulmonale Hypertonie: mikroRNAs in Pathogenese, Diagnostik und Therapie

Zusammenfassung

Im Unterschied zur pulmonal-arteriellen Hypertonie, welche eine seltene Erkrankung ist, umfasst der Überbegriff der pulmonalen Hypertonie ein klinisch häufigeres Krankheitsbild. Die pathophysiologische Trias von Vasokonstriktion, Mikrothrombosen und Gefäßumbau (Remodelling) findet sich dabei unabhängig von der zugrundeliegenden Entität in unterschiedlich starker Ausprägung bei praktisch allen Formen der pulmonalen Hypertonie. In dieser Übersichtsarbeit werden neue Aspekte in der Pathogenese des pulmonal-vaskulären Remodellings, insbesondere mikroRNA-abhängige Mechanismen, besprochen.

MikroRNAs sind kleine RNA-Fragmente, welche an die messengerRNA eines Zielgenes binden, was zum Abbau des Zielgenes oder zur Translationshemmung des betreffenden Gens führt („gene silencing“). Im Zusammenhang mit dem Gefäßumbau bei der pulmonalen Hypertonie ist vor allem die Assoziation von mikroRNAs und des Bone Morphogenetic Protein Rezeptor Typ II interessant: In verschiedenen Formen der pulmonalen Hypertonie wurde eine reduzierte Expression von Bone Morphogenetic Protein Rezeptor Typ II auf Endothelien und Gefäßmuskelzellen gefunden. Durch spezifische Hemmung mittels AntagomiRs bieten mikroRNAs die Möglichkeit für einen potenziell kausalen Therapieansatz. MikroRNAs werden zudem als Biomarker im Serum für Diagnose, Schweregrad und Prognose der pulmonalen Hypertonie validiert.

Abstract

Whereas pulmonary arterial hypertension is an orphan disease, the term pulmonary hypertension includes several common entities and is of major clinical significance. The pathophysiological triad of vasoconstriction, microthrombosis and vascular remodeling is found in most forms of pulmonary hypertension, independently of the underlying etiology. In this review, novel aspects in the pathogenesis of the remodeling, in particular microRNAs, will be discussed. MicroRNAs are small RNA fragments which bind specifically to the mRNA of a target gene thus decreasing its stability or inhibiting further translation (“gene silencing”). Of major interest is the association between microRNAs and the expression of bone morphogenetic protein receptor type II which has been found to be dysregulated on pulmonary endothelial and vascular smooth muscle cells in several forms of pulmonary hypertension. The specific inhibition of microRNAs by antagomiRs makes microRNAs a potential therapeutic target. Moreover, microRNAs are being validated in serum as biomarkers for diagnosis, severity and prognosis of pulmonary hypertension.

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