Lactate Dehydrogenase A Governs Cardiac Hypertrophic Growth in Response to Hemodynamic Stress

Area of Science:

• Cardiovascular Biology
• Metabolic Regulation
• Molecular Cardiology

Background:

• Cardiac hypertrophy is a response to hemodynamic stress, potentially leading to heart failure.
• Metabolic remodeling occurs early in cardiac hypertrophy, but its precise role is unclear.
• Lactate dehydrogenase A (LDHA) is a key glycolytic enzyme implicated in cellular metabolism.

Purpose of the Study:

• To investigate the role of lactate dehydrogenase A (LDHA) in cardiac hypertrophic growth and heart failure.
• To elucidate the molecular mechanisms by which LDHA influences cardiomyocyte growth under stress.

Main Methods:

• Utilized a cardiomyocyte-restricted LDHA deletion mouse model to assess cardiac function under pressure overload.
• Employed in vitro studies with cultured cardiomyocytes to examine LDHA's effect on cell growth.
• Investigated the downstream signaling pathways involving lactate, NDRG3 (N-myc downregulated gene family 3), and ERK (extracellular signal-regulated kinase).

Main Results:

• Cardiomyocyte-specific deletion of LDHA impaired cardiac hypertrophic growth and exacerbated heart failure during pressure overload.
• LDHA knockdown in cultured cardiomyocytes inhibited pro-hypertrophic growth, whereas LDHA overexpression promoted it.
• Lactate rescued the growth defect caused by LDHA knockdown, mediated by stabilization of NDRG3 and subsequent ERK activation.

Conclusions:

• LDHA is essential for adaptive cardiac hypertrophic growth in response to hemodynamic stress.
• The LDHA/NDRG3/ERK signaling axis plays a crucial role in regulating cardiomyocyte size and function.
• Targeting the LDHA pathway may offer therapeutic potential for managing stress-induced heart conditions.