MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation

Area of Science:

• Molecular Biology
• Cardiovascular Biology
• Signaling Pathways

Background:

• Stress-activated p38 kinases are crucial for cellular functions and implicated in diseases like cancer and obesity.
• Dysregulation of p38 kinases, including p38α, p38β, p38γ, and p38δ, activated by MKK3 and MKK6, is linked to various pathologies.
• p38 kinases are recognized as potential therapeutic targets.

Purpose of the Study:

• To investigate the role of MKK6 in mouse lifespan and cardiac function.
• To elucidate the molecular mechanisms underlying MKK6 deficiency-induced cardiac hypertrophy.
• To assess the therapeutic potential of targeting specific p38 pathway components or mTOR.

Main Methods:

• Generation and study of MKK6 knockout (KO) mice.
• Longitudinal assessment of cardiac function, including hypertrophy, dilatation, and fibrosis.
• Analysis of p38 kinase activation (p38α, p38γ, p38δ) and mammalian target of rapamycin (mTOR) signaling.
• Intervention studies involving genetic knockout of p38γ/δ or pharmacological inhibition of mTOR with rapamycin.

Main Results:

• MKK6 KO mice exhibited reduced lifespan and developed progressive cardiac hypertrophy, dilatation, and fibrosis.
• Lack of MKK6 led to blunted p38α activation but enhanced MKK3-p38γ/δ phosphorylation and increased mTOR signaling.
• Cardiac hypertrophy in MKK6 KO mice was ameliorated by knocking out p38γ or p38δ, or by rapamycin treatment.

Conclusions:

• The MKK3/6-p38γ/δ pathway plays a critical role in the development of cardiac hypertrophy.
• MKK6 deficiency-induced cardiotoxicity is mediated through p38γ/δ and mTOR signaling.
• These findings highlight potential cardiotoxicity risks associated with long-term p38α inhibitor use in clinical settings.