Abstract 20081: Distinct Signaling Pathways Mediate Phosphorylation of Sarcomeric Proteins in the Right and Left Ventricle of the Failing Heart

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Abstract

Introduction: Altered signaling pathways play a central role in sarcomeric dysfunction in the pathophysiology of heart failure (HF).

Hypothesis: Treatment options for HF are still limited maybe because of distinct remodeling processes and molecular mechanisms in the right (RV) and left ventricle (LV) of the failing heart.

Methods: Post-MI rats and HF patients with reduced ejection fraction were compared to sham-operated and healthy controls, respectively. LV and RV sarcomeric protein phosphorylation, protein kinase activity, phosphodiesterase (PDE) expression, myofilament calcium sensitivity (pCa50) and cardiomyocyte passive tension (Fpassive) were quantified.

Results: In HF rats LV pCa50 was higher compared to control, and was higher in the LV vs. RV. This goes along with decreased TnI phosphorylation in the LV and RV, and decreased MyBP-C phosphorylation but only in the RV. PDE2A, 3A and 9A expressions were increased, while PDE5A remained unaltered in the LV. Unexpectedly, all these PDEs were decreased in the RV. Fpassive was increased in both ventricles, but it was higher in the RV vs. LV. CaMKII treatment restored Fpassive in the RV but had no effect in the LV. PKG lowered Fpassive in both ventricles with more pronounced effect in the RV vs. LV. Titin phosphorylation was increased only at S12884 in the LV. Titin phosphorylation was decreased at S3991/S4080, increased at S4043, but unaltered at S12742/S12884 in the RV, because of distinct kinase activities of LV and RV. In biopsies from human HF pCa50 was higher in both ventricles compared to controls, and was higher in the LV vs. RV. TnI phosphorylation was decreased in the LV and RV, but MyBP-C phosphorylation was decreased only in the LV. Fpassive was increased in both ventricles and restored by PKG treatment with more pronounced effect in the LV vs. RV. Titin phosphorylation was unaltered at S4010/S4062/S12022, decreased at S4099, and increased at S11878 in the LV. Titin phosphorylation was decreased at S4010, increased at S4062/S11878/S12022, and unaltered at S4099 in the RV, because of distinct kinase activities of LV and RV.

Conclusions: Distinct kinase-mediated phosphorylation in the LV and RV in HF may have important therapeutic relevance when uniformly targeting cardiomyocyte signaling pathways.

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