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P38γ/δ activation alters cardiac electrical activity and predisposes to ventricular arrhythmia

ABSTRACT: Ventricular fibrillation (VF) is a leading immediate cause of sudden cardiac death. There is a strong association between aging and VF, although the mechanisms are unclear, limiting the availability of targeted therapeutic interventions. Here we found find that the stress kinases p38 and p38/are activated in the ventricles of old mice and mice with genetic or drug-induced arrhythmogenic conditions. We discovered that upon activation, the increased activity of p38 and p38/ was cooperatively associated increase the with susceptibility to stress-induced VF. Mechanistically, our data indicate that activated p38 and p38wphosphorylatee identified ryanodine receptor 2 (RyR2) and disrupt Kv4.3 channel localization, as a new substrate of p38/. Our data indicate that phosphorylation of SAP97 by activated p38/ also disrupts Kv4.3 localization at the plasma membrane, promoting sarcoplasmic reticulum calcium leak, Ito current reduction and action potential duration prolongation. In turn, this led to aberrant intracellular calcium handling, premature ventricular complexes, and enhanced susceptibility to VF. The importance of this finding is evidenced by the fact that bBlocking this pathway protected genetically modified animals from VF development and reduced the VF duration in aged animals. We have identified p38/-driven phosphorylation of RyR2 and SAP97 as a novel trigger of VF. These results indicate that p38 and p38/ are a new potential therapeutic target for sustained VF prevention.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

DISEASE(S): Cardiovascular System Disease

SUBMITTER: Juan A Lopez

LAB HEAD: Juan A Lopez

PROVIDER: PXD045996 | Pride | 2023-10-18

REPOSITORIES: Pride

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			Action	DRS
	JAL_GSB_RafaHeart_PhospProt_T4Z1234.raw	Raw
	JAL_GSB_RafaHeart_PhospProt_TZ_FrAll.raw	Raw
	JAL_GSB_RafaHeart_PhospProt_TZ_FrMix.raw	Raw
	JAL_GSB_RafaHeart_PhospProt_TZ_FrMix2.raw	Raw
	JAL_GSB_RafaHeart_PhospProt_T_Fr1.raw	Raw

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P38γ/δ activation alters cardiac electrical activity and predisposes to ventricular arrhythmia

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