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Heart failure-specific changes in protein kinase signalling
Kristina Lorenz1, Konstantina Stathopoulou, Evelyn Schmid
1Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, 97078, Würzburg, Germany, Lorenz@toxi.uni-wuerzburg.de.
Abstract:
Among the myriad of molecular alterations occurring in heart failure development, aggravation of the disease is often attributed to global or local changes in protein kinase activity, thus making protein kinases attractive targets for therapeutic intervention. Since protein kinases do not only have maladaptive roles, but also contribute to the physiological integrity of cells, it is a challenging task to circumvent undesired inhibition of protein kinase activity. Identification of posttranslational modifications and/or protein-protein interactions that are exclusively apparent under pathophysiological conditions provides exciting information for alternative non-kinase inhibitory treatment strategies that eliminate maladaptive functions of a protein kinase, but preserve the beneficial ones. Here, we focus on the disease-specific regulation of a number of protein kinases, namely, Ca(2+)/calmodulin-dependent protein kinase II isoform δ (CaMKIIδ), G protein-coupled receptor kinase 2 (GRK2), extracellular signal-regulated kinase 1 and 2 (ERK1/2), protein kinase D (PKD) and protein kinase C isoform β2 (PKCβ2), which are embedded in complex signal transduction pathways implicated in heart failure development, and discuss potential avenues for novel treatment strategies to combat heart disease.
Insights
Heart failure involves altered protein kinase activity. Targeting disease-specific protein kinase functions, not just inhibiting activity, offers novel therapeutic strategies for heart disease.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Biochemistry
Background:
- Heart failure progression is linked to altered protein kinase activity.
- Protein kinases have both detrimental and beneficial roles in cellular integrity.
- Developing targeted therapies requires understanding disease-specific kinase regulation.
Purpose of the Study:
- To identify disease-specific regulations of key protein kinases in heart failure.
- To explore novel, non-kinase inhibitory therapeutic strategies.
- To preserve beneficial kinase functions while eliminating maladaptive ones.
Main Methods:
- Focus on disease-specific regulation of CaMKIIδ, GRK2, ERK1/2, PKD, and PKCβ2.
- Analysis of posttranslational modifications and protein-protein interactions under pathophysiological conditions.
- Review of complex signal transduction pathways implicated in heart failure.
Main Results:
- Several protein kinases (CaMKIIδ, GRK2, ERK1/2, PKD, PKCβ2) show disease-specific regulation in heart failure.
- Pathophysiological conditions reveal unique modifications and interactions.
- These findings suggest avenues for targeted therapeutic interventions.
Conclusions:
- Targeting disease-specific functions of protein kinases offers a promising therapeutic approach for heart failure.
- Non-kinase inhibitory strategies can preserve beneficial kinase roles.
- Novel treatments can combat heart disease by selectively modulating maladaptive kinase activities.
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