Succinate causes pathological cardiomyocyte hypertrophy through GPR91 activation.

Area of Science:

• Cardiovascular Biology
• Metabolic Signaling
• Molecular Cardiology

Background:

• Succinate is a citric acid cycle intermediate and extracellular signaling molecule.
• G protein-coupled receptor-91 (GPR91) is a receptor for succinate identified in cardiac tissue.
• Ischemia increases circulating succinate levels, prompting investigation into its role in heart disease.

Purpose of the Study:

• To investigate the role of succinate in cardiac hypertrophy during ischemic events.
• To elucidate the signaling pathways involved in succinate-induced cardiac hypertrophy.

Main Methods:

• Utilized human and rodent models of cardiac ischemia.
• Assessed cardiac hypertrophy markers and signaling pathway activation.
• Measured serum succinate levels in patients with ischemic heart disease.

Main Results:

• Succinate induces cardiac hypertrophy in a GPR91-dependent manner.
• GPR91 activation leads to ERK1/2 phosphorylation, CaMKIIδ expression, and HDAC5 cytoplasmic translocation.
• Increased serum succinate levels were found in patients with hypertrophy linked to acute and chronic ischemia.

Conclusions:

• Succinate plays a significant role in cardiomyocyte hypertrophy via GPR91 activation.
• This study enhances understanding of how ischemia contributes to hypertrophic cardiomyopathy.