ACAD8 deficiency promotes pathological cardiac hypertrophy in response to pressure overload by regulating histone...

Area of Science:

• Biochemistry
• Molecular Biology
• Cardiovascular Research

Background:

• Branched-chain amino acids are crucial for heart function and disease.
• Genetic defects in valine metabolism enzyme ACAD8 link to cardiomyopathy, but its cardiac role is unclear.

Purpose of the Study:

• To define the role of ACAD8 in cardiac hypertrophy and dysfunction.
• To investigate the molecular mechanisms linking ACAD8 deficiency to cardiac pathology.

Main Methods:

• Analysis of ACAD8 levels in human and mouse cardiac hypertrophy models.
• Generation and analysis of cardiomyocyte-specific Acad8 knockout mice under pressure overload.
• Assessment of isobutyryl-CoA levels, histone isobutyrylation, and gene expression in cardiac tissues and cells.

Main Results:

• ACAD8 levels are decreased in human and male mouse cardiac hypertrophy.
• Cardiomyocyte-specific Acad8 knockout exacerbates hypertrophy and dysfunction in male mice.
• ACAD8 deficiency increases isobutyryl-CoA, leading to histone isobutyrylation, altered chromatin accessibility, and increased TEAD2 enrichment, promoting hypertrophy-related gene expression.
• ACAD8 overexpression mitigates these effects.

Conclusions:

• ACAD8 deficiency contributes to cardiac hypertrophy and dysfunction.
• Histone isobutyrylation, regulated by isobutyryl-CoA, plays a significant role in cardiac gene transcription and pathology.
• ACAD8 is a potential therapeutic target for cardiac diseases.