Defective Mitochondrial Respiration in Hereditary Thoracic Aneurysms

Area of Science:

• Cardiovascular Biology
• Mitochondrial Medicine
• Genetics of Aortic Disease

Background:

• Hereditary thoracic aortic aneurysms (TAADs) are linked to genetic disorders like Marfan syndrome.
• Traditionally, TAADs are attributed to extracellular matrix and smooth muscle cell defects.
• Emerging research implicates mitochondrial dysfunction in TAAD pathogenesis.

Purpose of the Study:

• To investigate the role of mitochondrial dysfunction in genetic forms of TAAD.
• To explore the therapeutic potential of NAD+ precursors in mitigating TAAD-associated pathology.
• To examine the impact of specific genetic mutations (ACTA2R179H, TGFBR2G357W) on vascular smooth muscle cell mitochondria.

Main Methods:

• Overexpression of ACTA2R179H and TGFBR2G357W in murine aortic vascular smooth muscle cells (VSMCs).
• Assessment of Mitochondrial Transcription Factor A (Tfam) expression and mitochondrial DNA (mtDNA) content.
• Analysis of oxidative phosphorylation, cellular metabolism (glycolysis), and actin polymerization.
• Evaluation of nicotinamide riboside (a NAD+ precursor) treatment effects on mitochondrial function and VSMC phenotype.

Main Results:

• ACTA2R179H and TGFBR2G357W overexpression reduced Tfam, mtDNA, and oxidative phosphorylation, promoting glycolysis.
• Nicotinamide riboside treatment restored mitochondrial respiration and increased Tfam and mtDNA levels.
• Nicotinamide riboside enhanced actin polymerization and reduced matrix metalloproteinase activity, promoting a contractile VSMC phenotype.

Conclusions:

• Mitochondrial dysfunction is a common feature in various genetic forms of thoracic aortic aneurysms.
• Targeting mitochondrial health via NAD+ boosters like nicotinamide riboside presents a promising therapeutic strategy for TAAD.
• This study expands the understanding of TAAD pathophysiology beyond traditional matrix and contractile defects.