PKG1α Cysteine-42 Redox State Controls mTORC1 Activation in Pathological Cardiac Hypertrophy

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Cellular Signaling

Background:

• Protein kinase G-1α (PKG1α) normally suppresses mTORC1 activation, mitigating pathological cardiac hypertrophy and dysfunction.
• Stressors can induce PKG1α oxidation at cysteine-42 (C42), blunting its cardioprotective function.
• Understanding the role of PKG1α oxidation in mTORC1 regulation is crucial for developing therapeutic strategies.

Purpose of the Study:

• To investigate the dependence of mTORC1 activation on PKG1α C42 oxidation.
• To determine if soluble guanylyl cyclase-1 (GC-1) activation can overcome the effects of PKG1α oxidation on mTORC1 signaling.
• To elucidate the mechanisms by which PKG1α regulates TSC2 phosphorylation and mTORC1 activity.

Main Methods:

• Utilized cardiomyocytes expressing wild-type (WT) PKG1α or a redox-dead mutant (PKG1α^CS/CS) exposed to endothelin-1 (ET-1).
• Employed global knock-in mice with PKG1α^CS/CS subjected to pressure overload (PO).
• Investigated TSC2 phosphorylation at serine 1365 (S1365) in PKG1α^CS/CS and TSC2 phospho-null (TSC2^{S1365A/S1365A}) models.

Main Results:

• PKG1α^WT cells/mice showed increased mTORC1 activation, reduced autophagy, and cardiac dysfunction under stress, which were reversed by PKG1α^CS/CS expression.
• PKG1α oxidation at C42 diminished TSC2-S1365 phosphorylation, amplifying PO-induced mTORC1 activity.
• Direct GC-1 stimulation ameliorated disparate mTORC1 activation and protected against cardiac pathology.

Conclusions:

• PKG1α oxidation at C42 impairs TSC2 phosphorylation, leading to enhanced mTORC1 activation and cardiac dysfunction during stress.
• Direct GC-1 stimulation offers a therapeutic approach to restore PKG1α function and protect the heart.
• Targeting the PKG1α-TSC2-mTORC1 axis holds promise for treating cardiovascular diseases.