GMRSP encoded by lncRNA H19 regulates metabolic reprogramming and alleviates aortic dissection

Area of Science:

• Vascular Biology
• Metabolic Regulation
• Molecular Medicine

Background:

• Metabolic disturbances in vascular smooth muscle cells (VSMCs) drive phenotypic transitions crucial in aortic dissection (AD) pathogenesis.
• Understanding VSMC metabolic regulation is key to developing effective AD therapies.

Purpose of the Study:

• To identify and characterize the role of glucose metabolism regulatory protein (GMRSP) in VSMC phenotype and AD.
• To elucidate the molecular mechanisms by which GMRSP influences VSMC metabolism and stability.
• To evaluate GMRSP as a potential therapeutic target for AD.

Main Methods:

• Generated VSMC-specific GMRSP induction in knock-in mice.
• Utilized adeno-associated virus-mediated GMRSP overexpression and exosomal GMRSP delivery.
• Investigated GMRSP's effect on pyruvate kinase M (PKM) splicing and glycolysis.
• Assessed the impact of PKM2 activation (TEPP-46) on GMRSP's protective effects.
• Analyzed plasma PKM2 levels in AD patients.

Main Results:

• GMRSP induction/overexpression significantly improved AD and mitochondrial dysfunction.
• GMRSP inhibits hnRNP A2B1-mediated PKM alternative splicing, reducing PKM2 and glycolysis.
• This metabolic reprogramming preserved VSMC contractile phenotype and prevented proliferative transition.
• Pharmacological PKM2 activation abrogated GMRSP's protective effects in vitro and in vivo.
• Elevated plasma PKM2 levels in AD patients correlated with poor prognosis.

Conclusions:

• GMRSP is a critical regulator of VSMC metabolism and phenotypic stability.
• GMRSP's mechanism involves modulating PKM splicing and glycolysis.
• GMRSP demonstrates significant therapeutic potential for treating aortic dissection.