Overlapping and differential functions of ATF6α versus ATF6β in the mouse heart

Area of Science:

• Cardiology
• Molecular Biology
• Cellular Stress Response

Background:

• Hemodynamic stress induces cardiac hypertrophy and endoplasmic reticulum (ER) stress.
• Activating transcription factor 6α (ATF6α) is activated during ER stress in cardiac myocytes.
• The specific roles of ATF6α and ATF6β in cardiac response to pressure overload are not fully understood.

Purpose of the Study:

• To investigate the roles of ATF6α and ATF6β in the cardiac response to pressure overload.
• To determine the impact of ATF6α and ATF6β deficiency on cardiac hypertrophy and function under stress.

Main Methods:

• Utilized gene-deleted mice lacking Atf6 or Atf6b.
• Subjected mice to transverse aortic constriction to induce pressure overload.
• Analyzed cardiac hypertrophy, ER stress markers, and cardiac function.

Main Results:

• Short-term pressure overload in Atf6 or Atf6b null mice showed reduced hypertrophy and ER stress markers.
• Long-term pressure overload led to enhanced cardiac decompensation, including increased heart weight, pulmonary edema, and reduced function in null mice.
• Transgenic mice expressing ATF6α or ATF6β revealed overlapping gene networks regulating ER protein chaperones and degradation.

Conclusions:

• ATF6α and ATF6β play critical, previously unappreciated roles in regulating cardiac hypertrophy in response to pressure overload.
• These transcription factors are essential for maintaining cardiac function and ER homeostasis during prolonged hemodynamic stress.