Abstract
PRKAG2 cardiomyopathy is a rare progressive disease characterized by increased ventricular wall thickness and preexcitation. Dysfunction of the protein 5′-AMP-activated protein kinase (AMPK) plays a decisive role in the progression of ventricular lesions. Although patients with the PRKAG2-R302Q mutation have a high incidence of atrial fibrillation (AF), the molecular mechanism contributing to the disease remains unclear. We carried out whole-genome sequencing with linkage analysis in three affected members of a family. Atrial samples were obtained from the proband via surgical intervention. Control atrium biopsies were obtained from patients with persistent AF. Pathological changes were analyzed using the hematoxylin and eosin (H&E), Masson, and periodic acid–Schiff (PAS) staining. The AMPK signaling pathway was investigated by western blot. A murine atrial cardiomyocyte cell line (HL-1) and human induced pluripotent stem derived atrial cardiomyocytes (hiPSC-ACMs) were transfected with an adenovirus carrying the same mutation. We used enzyme linked immunosorbent assay (ELISA) to determine the AMPK activity in HL-1 cells and hiPSC-ACMs overexpressing PRKAG2-R302Q. Pathological results showed a large quantity of glycogen accumulation and vacuolization in cardiomyocytes from the proband atrial tissue. Western blot analysis revealed that the AMPK activity was significantly downregulated compared with that of the controls. Furthermore, remarkable glycogen deposition and impairment of AMPK activity were reproduced in HL-1 cells overexpressing PRKAG2-R302Q. Taken together, PRKAG2-R302Q mutation directly impair atrial cardiomyocytes. PRKAG2-R302Q mutation lead to glycogen deposition and promote the growth of atrial lesions by disrupting the AMPK pathway.
Highlights
MATERIALS AND METHODSThe PRKAG2 gene was mapped to chromosome 7, encoding the γ2 subunit of AMP-activated protein kinase (AMPK) [1]
Our results provide solid pathological evidence of atrial lesions caused by the PRKAG2-R302Q mutation, as well as evidence of an impaired AMPK protein activation mode in response to different stimuli, shedding light on potential therapeutic strategies for atrial cardiomyopathy
Considering that left atrial hemodynamics can be altered by atrial flutter, the left atrial appendage (LAA) was analyzed in detail using enhanced cardiac CT scans
Summary
The PRKAG2 gene was mapped to chromosome 7, encoding the γ2 subunit of AMP-activated protein kinase (AMPK) [1]. Different ratios of AMP/ATP binding to the γ2 subunit result in different levels of AMPK activity. Increased activity of the insulin pathway, a widely accepted hypertrophic signal, was found to be responsible for cardiomyocyte hypertrophy caused by the PRKAG2 gene mutation [9]. Patient-specific induced pluripotent stem cell (iPSC)-derived cardiomyocytes have exhibited increased AMPK activities [11, 12]. Patient-specific iPSC-CMs harbor the same gene background as the host, these cells are immature compared to adult cardiomyocytes, including in terms of metabolic properties. Our results provide solid pathological evidence of atrial lesions caused by the PRKAG2-R302Q mutation, as well as evidence of an impaired AMPK protein activation mode in response to different stimuli, shedding light on potential therapeutic strategies for atrial cardiomyopathy. A p-value < 0.05 was considered statistically significant
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