Pioglitazone Alleviates β1-Adrenergic Receptor Antibody-Induced Atrial Fibrillation Susceptivity via Mitigation of PPAR-γ-Mediated
Metabolic Inflexibility
Authors: Xi Linqiang , Sun Huaxin , Yang Na , Wang Qianhui , Zhang Ling , Song Jie , Taiwaikuli Dilare , Shang Luxiang , Zhou Xian hui 
Published: May 2024

Background:
Beta-1-adrenergic receptor antibodies (β1-AAbs) function as arrhythmogenic
molecules in autoimmune-related atrial fibrillation (AF). This study examined the potential impact
of pioglitazone, an agonist for peroxisome proliferator-activated receptor-γ (PPAR-γ), on atrial
remodeling induced by β1-AAbs.

Methods:
An in vivo study was performed to confirm the protective effects of pioglitazone on β1-
AAbs-induced atrial remodeling. GW9662, a PPAR-γ antagonist, was employed to identify the potential
therapeutic target of pioglitazone. The rats were administered subcutaneous injections of the
second extracellular loop peptide for 8 weeks to establish active immunization models. Pioglitazone
was then administered orally for 2 weeks. Epicardial electrophysiologic studies, multielectrode array
measurements, and echocardiography were conducted to examine atrial remodeling. Glucose
metabolism products and key metabolic molecules were measured to evaluate the atrial substrate
metabolism. Mitochondrial morphologies and function indices were tested to depict the underlying
links between atrial metabolism and mitochondrial homeostasis under the pioglitazone treatment.

Results:
Pioglitazone significantly reversed β1-AAbs-induced AF susceptibility, ameliorated atrial
structural remodeling, decreased the global insulin resistance reflected in the plasma glucose and insulin
levels, and increased the protein expressions of glycolipid uptake and transportation (GLUT1,
CD36, and CPT1a). These trends were counterbalanced by the GW9662 intervention. Mechanistically,
pioglitazone mitigated the atrial mitochondrial network damage and partly renovated the mitochondrial
biogenesis, even the mitochondrial dynamics, which were reversed by inhibiting the
PPAR-γ target.

Conclusion:
Pioglitazone effectively reduced the AF vulnerability and recovered the atrial myocardial
metabolism and mitochondrial damage. The potential anti-remodeling effect of pioglitazone on
the atrium was associated with the moderately increased expression of key membrane proteins related
to glucose transporter and fatty acid uptake, which may promote the increased myocardial preference
for utilization of FA as the key cardiac oxidative fuel and ameliorate the atrial metabolic inflexibility.

result:
Functional enrichment analysis revealed that the PPAR pathway is downregulated in active immunization animal models. Pioglitazone significantly reversed β1-AAbs-induced AF susceptibility and ameliorated atrial structural remodeling, decreased the global insulin resistance reflected in the plasma glucose and insulin levels, and increased the protein expressions of glycolipid uptake and transportation (GLUT1, CD36, and CPT1a), these trends were counterbalanced by the GW9662 intervention. Mechanistically, pioglitazone mitigated the atrial mitochondrial network damage and partly renovated the mitochondrial biogenesis, even the mitochondrial dynamics, which were reversed by inhibiting the PPAR-γ target.