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I microRNA-24 regolano la funzione endoteliale e l'angiogenesi

Apoptosi dell'endotelio e insufficiente densità capillare sono responsabili dell'estensione dell'area infartuata e dell'insufficienza ventricolare sinistra in corso di infarto acuto del miocardio.
In questi fenomeni un ruolo di rilievo viene svolto da alcune sottoclassi di microRNA, in particolare microRNA-24, che vengono regolati dalla tensione di ossigeno tessutale. I microRNA sono piccole molecole non codificanti che regolano però parti consistenti del genoma e sono già stati identificati come possibili obiettivi terapeutici per molte malattie, incluse quelle cardiovascolari.
In questo studio i microRNA-24 sono risultati essere importanti regolatori della sopravvivenza delle cellule endoteliali e dell'angiogenesi. La loro inibizione ridurrebbe l'apoptosi delle cellule endoteliali, aumenterebbe la vascolarizzazione e ridurrebbe l'estensione dell'area ischemica e necrotica dopo infarto acuto del miocardio.

MicroRNA-24 regulates vascularity after myocardial infarction

Fiedler J, Jazbutyte V, Kirchmaier BC, Gupta SK, Lorenzen J, Hartmann D, Galuppo P, Kneitz S, Pena JT, Sohn-Lee C, Loyer X, Soutschek J, Brand T, Tuschl T, Heineke J, Martin U, Schulte-Merker S, Ertl G, Engelhardt S, Bauersachs J, Thum T.

Circulation 2011;124:720-30

BACKGROUND: Myocardial infarction leads to cardiac remodeling and development of heart failure. Insufficient myocardial capillary density after myocardial infarction has been identified as a critical event in this process, although the underlying mechanisms of cardiac angiogenesis are mechanistically not well understood.
METHODS AND RESULTS: Here, we show that the small noncoding RNA microRNA-24 (miR-24) is enriched in cardiac endothelial cells and considerably upregulated after cardiac ischemia. MiR-24 induces endothelial cell apoptosis, abolishes endothelial capillary network formation on Matrigel, and inhibits cell sprouting from endothelial spheroids. These effects are mediated through targeting of the endothelium-enriched transcription factor GATA2 and the p21-activated kinase PAK4, which were identified by bioinformatic predictions and validated by luciferase gene reporter assays. Respective downstream signaling cascades involving phosphorylated BAD (Bcl-XL/Bcl-2-associated death promoter) and Sirtuin1 were identified by transcriptome, protein arrays, and chromatin immunoprecipitation analyses. Overexpression of miR-24 or silencing of its targets significantly impaired angiogenesis in zebrafish embryos. Blocking of endothelial miR-24 limited myocardial infarct size of mice via prevention of endothelial apoptosis and enhancement of vascularity, which led to preserved cardiac function and survival.
CONCLUSIONS: Our findings indicate that miR-24 acts as a critical regulator of endothelial cell apoptosis and angiogenesis and is suitable for therapeutic intervention in the setting of ischemic heart disease.

Circulation 2011;124:720-30