MLK3 mediates impact of PKG1α on cardiac function and controls blood pressure through separate mechanisms

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Pharmacology

Background:

• cGMP-dependent protein kinase 1α (PKG1α) aids left ventricle (LV) compensation in pressure overload models.
• PKG1-activating drugs show promise for heart failure (HF) but cause hypotension.
• Identifying targets mediating PKG1α cardiac effects without systemic vasodilation is crucial.

Purpose of the Study:

• To investigate the role of mixed lineage kinase 3 (MLK3) in mediating PKG1α's effects on LV function and blood pressure (BP) regulation after pressure overload.
• To determine if MLK3 is a substrate of PKG1α and if this interaction is altered in HF.

Main Methods:

• Utilized a transaortic constriction mouse model to induce pressure overload and HF.
• Employed PKG activation (sildenafil) and inhibition (URMC-099) strategies.
• Performed co-immunoprecipitation assays to assess MLK3-PKG1α interaction.
• Analyzed LV function, BP, and arterial stiffness in wild-type and MLK3 knockout mice.

Main Results:

• PKG activation preserved LV function in wild-type mice but not in MLK3 knockout mice.
• MLK3 co-immunoprecipitated with PKG1α, and this interaction decreased in failing LVs.
• PKG1α phosphorylated MLK3 on activation sites (Thr277/Ser281).
• MLK3 knockout mice exhibited hypertension and increased arterial stiffness.
• MLK3 kinase-dependent signaling preserved LV function, while MLK3 kinase-independent signaling regulated BP.

Conclusions:

• MLK3 acts as a substrate for PKG1α, mediating its beneficial effects on LV function in pressure overload.
• MLK3 is essential for PKG1α-mediated cardiac protection but not for PKG1α's acute blood pressure effects.
• Targeting MLK3 kinase activity represents a potential therapeutic strategy for HF to preserve cardiac function while avoiding hypotension.