Gabapentin and α2δ1 C-terminal peptide reduce left atrial hypertrophy in ischemic heart failure rats

Left atrial remodeling (LAR) is a critical driver in the progression of heart failure (HF) and the development of atrial fibrillation (AF) following myocardial infarction (MI). Current therapies often fall short in adequately targeting the complex mechanisms underlying LAR. The protein α2δ1, while primarily recognized for its role in neuropathic pain, is highly expressed in atrial tissue. Its specific involvement in post-MI LAR and its potential as a therapeutic target for cardiac remodeling have remained largely unexplored, representing a significant gap in understanding and treatment strategies.

Researchers established LAR models in rats post-myocardial infarction (MI) and induced atrial hypertrophy in HL-1 cells using angiotensin II (AngII). The role of α2δ1 in atrial hypertrophy was investigated by treating cells with either the α2δ1 inhibitor gabapentin or a C-terminal interfering peptide (α2δ1 CT-pep). Key endpoints included HL-1 cell hypertrophy, CAMKII and HDAC4 phosphorylation via Western blot, α2δ1-GluN1 interaction via co-immunoprecipitation, and GluN1 membrane translocation. In MI rats, gabapentin treatment was assessed for its effects on atrial hypertrophy, AF inducibility and duration, and membrane-associated α2δ1 and GluN1 levels.

A significant upregulation of α2δ1 expression was observed in the left atrium (LA) of MI rats and in AngII-treated HL-1 cells. Western blot analysis showed increased α2δ1 levels in membrane fractions and decreased levels in cytoplasmic fractions compared to controls. Both gabapentin and α2δ1 CT-pep treatment significantly reduced HL-1 cell hypertrophy and inhibited CAMKII and HDAC4 phosphorylation. Co-immunoprecipitation assays demonstrated an interaction between α2δ1 and GluN1, which was enhanced by AngII stimulation. Inhibition of α2δ1 attenuated this α2δ1-GluN1 interaction and reduced GluN1 translocation to the plasma membrane. > In MI-induced HF rats, gabapentin treatment diminished atrial hypertrophy, suppressed AF inducibility and duration, and decreased membrane-associated α2δ1 and GluN1 levels. These findings collectively suggest a crucial role for the α2δ1 C-terminal domain in left atrial hypertrophy.