Cardiac dysfunction and altered gene expression in acid ceramidase-deficient mice.

Area of Science:

• Biochemistry
• Genetics
• Cardiology

Background:

• Farber disease (FD) is an ultrarare lysosomal storage disorder caused by ASAH1 gene mutations.
• FD leads to acid ceramidase deficiency and ceramide accumulation, affecting multiple organs.
• Cardiac involvement in FD is recognized but not well-characterized.

Purpose of the Study:

• To investigate cardiac pathophysiology in a novel P361R-FD mouse model.
• To elucidate the role of acid ceramidase in cardiac development and function.
• To characterize the impact of acid ceramidase deficiency on cardiac structure and performance.

Main Methods:

• Generation and analysis of a P361R-FD mouse model.
• Echocardiography to assess cardiac function.
• Histopathological analysis of heart tissue.
• Biochemical analysis of lipid content.
• Gene expression analysis of cardiac-related pathways.

Main Results:

• P361R-FD mice exhibited smaller hearts, altered cardiomyocyte structure, and tissue disruption.
• Echocardiography revealed ventricular atrophy, valve dysfunction, and reduced cardiac output.
• Elevated Troponin I and increased ceramide/cholesterol levels were observed.
• Lysosomal disruption was evident as early as postnatal day 1.
• Aberrant gene expression related to cardiac conduction and sphingolipid metabolism was detected.

Conclusions:

• Acid ceramidase deficiency induces significant cardiac dysfunction in the P361R-FD mouse model.
• Lysosomal dysfunction, sphingolipid imbalance, and inflammation contribute to cardiac pathology.
• This model provides crucial insights into FD-related heart disease and the role of ceramides in cardiac health.