Long Non-Coding RNA MALAT1 Regulates HMOX1 in Sickle Cell Disease-Associated Pulmonary Hypertension

Area of Science:

• Vascular Biology
• Genomics
• Hematology

Background:

• Pulmonary hypertension (PH) is a serious complication of sickle cell disease (SCD).
• Endothelial dysfunction, triggered by heme release during hemolysis, contributes to PH in SCD.
• Long non-coding RNAs (lncRNAs) are implicated in endothelial dysfunction and PH pathogenesis.

Purpose of the Study:

• To investigate the regulatory role of the lncRNA-heme oxygenase-1 (HMOX1) axis in SCD-associated PH.
• To determine the function of MALAT1 in endothelial homeostasis and PH in SCD models.

Main Methods:

• lncRNA expression profiling in lungs of sickle cell (SS) mice and controls (AA).
• Quantitative PCR validation of differentially expressed lncRNAs.
• In vitro studies using hemin-treated human pulmonary artery endothelial cells (HPAECs).
• In vivo studies involving adenoviral MALAT1 overexpression in SS mice.

Main Results:

• MALAT1 was significantly upregulated in SS mice lungs and hemin-treated HPAECs.
• MALAT1 depletion worsened endothelial dysfunction markers (ET-1, VCAM1), while overexpression improved them.
• MALAT1 overexpression attenuated PH, right ventricular hypertrophy, and vascular remodeling in SS mice.
• MALAT1 induction of HMOX1 expression and activity was observed, mitigating endothelial dysfunction.

Conclusions:

• MALAT1 acts as a protective regulator against endothelial dysfunction, vascular remodeling, and PH in SCD.
• The MALAT1-HMOX1 axis plays a crucial role in SCD-associated PH pathogenesis.
• MALAT1 modulation represents a potential therapeutic strategy for SCD-related PH.