ER Stress-Response Signaling Regulates Chamber-Specific Growth between Right and Left Ventricles during Postnatal...

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Developmental Biology

Background:

• Differential growth between the left ventricle (LV) and right ventricle (RV) is essential for normal heart development, resulting in a larger LV in adults.
• Factors regulating this chamber-specific growth remain largely unknown.

Purpose of the Study:

• To investigate the role of the IRE1α-Xbp1 pathway in regulating differential ventricular growth.
• To identify downstream targets of spliced Xbp1 (sXbp1) involved in cardiomyocyte function.

Main Methods:

• Utilized mouse models with genetic or pharmacological manipulation of IRE1α or Xbp1 in cardiomyocytes.
• Employed primary cultured neonatal cardiomyocytes and CRISPR/Cas9/AAV9-based somatic mutagenesis.
• Generated heart-specific mosaic mutant mouse models to study sXbp1 downstream targets.

Main Results:

• Inactivation of IRE1α or Xbp1 led to smaller LV size, reduced cardiomyocyte proliferation, and increased cell death, without affecting the RV.
• Induction of IRE1α or sXbp1 enhanced ventricular size by promoting cardiomyocyte proliferation and growth, and reducing apoptosis.
• Identified Vimp and Rpn2 as direct binding partners of sXbp1, regulating cardiomyocyte proliferation, growth, and death, with observed protein misfolding in mutants.

Conclusions:

• The IRE1α-Xbp1-Vimp/Rpn2 axis orchestrates differential ventricular size during postnatal development by controlling cardiomyocyte proliferation, hypertrophic growth, and death.
• This pathway regulates protein homeostasis, impacting heart development and potentially offering therapeutic avenues for heart conditions.