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

Autor:	Calamaras TD; Molecular Cardiology Research Institute and., Pande S; Molecular Cardiology Research Institute and., Baumgartner RA; Molecular Cardiology Research Institute and., Kim SK; Molecular Cardiology Research Institute and., McCarthy JC; Molecular Cardiology Research Institute and., Martin GL; Molecular Cardiology Research Institute and., Tam K; Molecular Cardiology Research Institute and., McLaughlin AL; Molecular Cardiology Research Institute and., Wang GR; Molecular Cardiology Research Institute and., Aronovitz MJ; Molecular Cardiology Research Institute and., Lin W; Molecular Cardiology Research Institute and.; Graduate School of Biomedical Sciences, Tufts University, Boston, Massachusetts, USA., Aguirre JI; Molecular Cardiology Research Institute and., Baca P; Molecular Cardiology Research Institute and.; Graduate School of Biomedical Sciences, Tufts University, Boston, Massachusetts, USA., Liu P; Molecular Cardiology Research Institute and.; Graduate School of Biomedical Sciences, Tufts University, Boston, Massachusetts, USA., Richards DA; Molecular Cardiology Research Institute and., Davis RJ; University of Massachusetts School of Medicine, Worchester, Massachusetts, USA., Karas RH; Molecular Cardiology Research Institute and., Jaffe IZ; Molecular Cardiology Research Institute and.; Graduate School of Biomedical Sciences, Tufts University, Boston, Massachusetts, USA., Blanton RM; Molecular Cardiology Research Institute and.; Graduate School of Biomedical Sciences, Tufts University, Boston, Massachusetts, USA.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2021 Sep 22; Vol. 6 (18). Date of Electronic Publication: 2021 Sep 22.
DOI:	10.1172/jci.insight.149075
Abstrakt:	cGMP-dependent protein kinase 1α (PKG1α) promotes left ventricle (LV) compensation after pressure overload. PKG1-activating drugs improve heart failure (HF) outcomes but are limited by vasodilation-induced hypotension. Signaling molecules that mediate PKG1α cardiac therapeutic effects but do not promote PKG1α-induced hypotension could therefore represent improved therapeutic targets. We investigated roles of mixed lineage kinase 3 (MLK3) in mediating PKG1α effects on LV function after pressure overload and in regulating BP. In a transaortic constriction HF model, PKG activation with sildenafil preserved LV function in MLK3+/+ but not MLK3-/- littermates. MLK3 coimmunoprecipitated with PKG1α. MLK3-PKG1α cointeraction decreased in failing LVs. PKG1α phosphorylated MLK3 on Thr277/Ser281 sites required for kinase activation. MLK3-/- mice displayed hypertension and increased arterial stiffness, though PKG stimulation with sildenafil or the soluble guanylate cyclase (sGC) stimulator BAY41-2272 still reduced BP in MLK3-/- mice. MLK3 kinase inhibition with URMC-099 did not affect BP but induced LV dysfunction in mice. These data reveal MLK3 as a PKG1α substrate mediating PKG1α preservation of LV function but not acute PKG1α BP effects. Mechanistically, MLK3 kinase-dependent effects preserved LV function, whereas MLK3 kinase-independent signaling regulated BP. These findings suggest augmenting MLK3 kinase activity could preserve LV function in HF but avoid hypotension from PKG1α activation.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu