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Targeting the CaMKII/ERK Interaction in the Heart Prevents Cardiac Hypertrophy
Ersilia Cipolletta1, Maria Rosaria Rusciano2, Angela Serena Maione2
1Department of Medicine and Surgery, University of Salerno, Baronissi (SA), Italy.
Aims:
Activation of Ca2+/Calmodulin protein kinase II (CaMKII) is an important step in signaling of cardiac hypertrophy. The molecular mechanisms by which CaMKII integrates with other pathways in the heart are incompletely understood. We hypothesize that CaMKII association with extracellular regulated kinase (ERK), promotes cardiac hypertrophy through ERK nuclear localization.
Methods And Results:
In H9C2 cardiomyoblasts, the selective CaMKII peptide inhibitor AntCaNtide, its penetratin conjugated minimal inhibitory sequence analog tat-CN17β, and the MEK/ERK inhibitor UO126 all reduce phenylephrine (PE)-mediated ERK and CaMKII activation and their interaction. Moreover, AntCaNtide or tat-CN17β pretreatment prevented PE induced CaMKII and ERK nuclear accumulation in H9C2s and reduced the hypertrophy responses. To determine the role of CaMKII in cardiac hypertrophy in vivo, spontaneously hypertensive rats were subjected to intramyocardial injections of AntCaNtide or tat-CN17β. Left ventricular hypertrophy was evaluated weekly for 3 weeks by cardiac ultrasounds. We observed that the treatment with CaMKII inhibitors induced similar but significant reduction of cardiac size, left ventricular mass, and thickness of cardiac wall. The treatment with CaMKII inhibitors caused a significant reduction of CaMKII and ERK phosphorylation levels and their nuclear localization in the heart.
Conclusion:
These results indicate that CaMKII and ERK interact to promote activation in hypertrophy; the inhibition of CaMKII-ERK interaction offers a novel therapeutic approach to limit cardiac hypertrophy.
Insights
Inhibiting the interaction between Ca2+/Calmodulin protein kinase II (CaMKII) and extracellular regulated kinase (ERK) reduces cardiac hypertrophy. This CaMKII-ERK pathway is a novel therapeutic target for limiting heart enlargement.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Cell Signaling
Background:
- Cardiac hypertrophy involves Ca2+/Calmodulin protein kinase II (CaMKII) activation.
- The integration of CaMKII with other signaling pathways in the heart is not fully understood.
Purpose of the Study:
- To investigate the hypothesis that CaMKII association with extracellular regulated kinase (ERK) promotes cardiac hypertrophy via ERK nuclear localization.
- To explore the therapeutic potential of inhibiting the CaMKII-ERK interaction.
Main Methods:
- Utilized H9C2 cardiomyoblasts and spontaneously hypertensive rat models.
- Employed CaMKII inhibitors (AntCaNtide, tat-CN17β) and an MEK/ERK inhibitor (UO126).
- Assessed protein activation, nuclear localization, and cardiac hypertrophy markers via cell assays and echocardiography.
Main Results:
- CaMKII and ERK inhibitors reduced phenylephrine-induced activation and interaction of CaMKII and ERK in H9C2 cells.
- Inhibition of CaMKII prevented nuclear accumulation of CaMKII and ERK and reduced hypertrophy responses in cells.
- In vivo, CaMKII inhibitors significantly reduced cardiac size, left ventricular mass, and cardiac wall thickness in hypertensive rats.
- Treatment decreased CaMKII and ERK phosphorylation and nuclear localization in the heart.
Conclusions:
- CaMKII and ERK interact to drive activation during cardiac hypertrophy.
- Inhibiting the CaMKII-ERK interaction presents a novel therapeutic strategy for managing cardiac hypertrophy.
