MALAT1 promotes platelet activity and thrombus formation through PI3k/Akt/GSK-3β signalling pathway

Area of Science:

• * Molecular Biology
• * Hematology
• * Cardiovascular Research

Background:

• * Platelet activity is crucial for hemostasis and thrombosis, processes often abnormal in cardiovascular diseases like ischemic stroke.
• * Platelets contain numerous long non-coding RNAs (lncRNAs), which may regulate gene expression post-transcriptionally due to the absence of a nucleus.
• * The specific roles of lncRNAs in platelet function remain largely unexplored.

Purpose of the Study:

• * To elucidate the molecular mechanism by which MALAT1 influences platelet activity.
• * To investigate the role of MALAT1 in thrombus formation.

Main Methods:

• * Utilized CD34+ megakaryocytes as an in vitro model for human megakaryocytes and platelets.
• * Performed MALAT1 knockdown (KD) experiments in megakaryocytes and analyzed platelet-like particle function.
• * Employed a microfluidic whole-blood perfusion model to assess thrombus development on a collagen matrix.
• * Studied MALAT1-deficient mice to evaluate bleeding time and thrombus formation in vivo.
• * Investigated the regulatory role of PTEN and PDK1 in MALAT1's PI3k/Akt/GSK-3β signaling pathway function.

Main Results:

• * MALAT1 knockdown in megakaryocytes enhanced cell adhesion and spreading.
• * Platelet-like particles from MALAT1 KD cells showed significantly increased adhesion and activity, both at rest and upon thrombin activation.
• * Microfluidic studies revealed enhanced thrombus development, with MALAT1-deficient platelets exhibiting increased accumulation, area coverage, and activity.
• * MALAT1-deficient mice demonstrated reduced bleeding times and faster formation of stable occlusive thrombi compared to wild-type mice.
• * PTEN and PDK1 were identified as regulators of MALAT1 activity within platelets, influencing the PI3k/Akt/GSK-3β signaling pathway.

Conclusions:

• * Suppression of MALAT1 expression significantly augments platelet adhesion, spreading, activity, and thrombus formation.
• * lncRNAs represent a distinct class of modulators for platelet function.
• * MALAT1 plays a critical role in regulating platelet hemostatic potential.