Macrophages Lacking TSC2 have mTORC1-dependent GPNMB Augmentation Ameliorating Cardiac Ischemia-Reperfusion Injury

Area of Science:

• Cardiovascular Biology
• Immunology
• Molecular Medicine

Background:

• Macrophages (MΦ) play a dual role in myocardial ischemia-reperfusion (I/R) injury, influencing both inflammation and repair.
• The mechanistic target of rapamycin (mTOR) pathway is implicated in MΦ function, but its precise role in I/R injury is context-dependent.

Purpose of the Study:

• To investigate the impact of constitutive macrophage-specific mTORC1 activation on cardiac responses to I/R injury.
• To determine if targeted deletion of tuberous sclerosis complex 2 (TSC2) in MΦ influences I/R outcomes.

Main Methods:

• Generated myeloid-specific TSC2-deficient (MΦ ^TSC2-/-) mice.
• Assessed MΦ phenotype and response to stimuli in vitro and in vivo post-I/R.
• Utilized rapamycin to confirm mTORC1 dependence.

Main Results:

• MΦ ^TSC2-/- mice exhibited significant protection against I/R injury, with preserved ejection fraction and reduced cardiac remodeling.
• These mice showed decreased infiltration of pro-inflammatory cells and enhanced expression of the anti-inflammatory protein GPNMB.
• Rapamycin treatment reversed the protective effects, confirming mTORC1 pathway involvement.

Conclusions:

• Constitutive MΦ mTORC1 activation via TSC2 deletion confers cardioprotection against I/R injury.
• This protection is mediated by reduced inflammation and increased GPNMB expression.
• The mTORC1-GPNMB signaling axis in MΦ represents a potential therapeutic target for I/R injury.