The role of desmin alterations in mechanical electrical feedback in heart failure

Area of Science:

• Cardiovascular Physiology
• Molecular Cardiology
• Cellular Mechanotransduction

Background:

• Mechanoelectric feedback (MEF) plays a critical role in cardiac electrical stability, with its dysfunction implicated in malignant arrhythmias observed in heart failure (HF).
• Desmin, a key cytoskeletal protein, is hypothesized to act as a mechanoelectrical transducer, potentially mediating MEF alterations in the context of HF.

Purpose of the Study:

• To investigate the role of desmin alterations in mechanoelectric feedback within a heart failure model.
• To elucidate the underlying molecular mechanisms by which desmin influences cardiac electrical activity and calcium handling in HF.

Main Methods:

• Employed both in vivo rat models (sham, HF, streptomycin, MDL-28170) and an in vitro cardiomyocyte model (NC, si-desmin, si-desmin + NBD IKK).
• Assessed ventricular arrhythmias (VA), desmin expression, NF-κB pathway activation (IKKβ, p-IKKβ, IKBα, p-NF-κB), SERCA2 levels, and intracellular calcium (Ca2+) handling.

Main Results:

• Heart failure significantly increased ventricular arrhythmias; desmin breakdown correlated with VA occurrence.
• Desmin knockdown in cardiomyocytes activated the NF-κB pathway, reduced SERCA2 expression, and caused abnormal Ca2+ distribution.
• NF-κB inhibition restored SERCA2 levels and alleviated Ca2+ handling abnormalities.

Conclusions:

• Desmin appears to modulate mechanoelectric feedback in heart failure, potentially through activation of the NF-κB signaling pathway.
• These findings highlight desmin and the NF-κB pathway as potential therapeutic targets for managing ventricular arrhythmias in heart failure patients.