Cardiac dysfunction and altered gene expression in acid ceramidase-deficient mice. Am J Physiol Heart Circ Physiol 2025 Jan 01;328(1):H141-H156
Date
12/12/2024Pubmed ID
39665198Pubmed Central ID
PMC12233101DOI
10.1152/ajpheart.00289.2024Scopus ID
2-s2.0-85213996641 (requires institutional sign-in at Scopus site) 3 CitationsAbstract
Farber disease (FD) is an ultrarare, autosomal-recessive, lysosomal storage disorder attributed to ASAH1 gene mutations. FD is characterized by acid ceramidase (ACDase) deficiency and the accumulation of ceramide in various tissues. Classical FD patients typically manifest symptoms including lipogranulomatosis, respiratory complications, and neurological deficits, often leading to mortality during infancy. Cardiac abnormalities in several FD patients have been described; however, a detailed examination of cardiac pathology in FD has not been conducted. Here we report pronounced cardiac pathophysiology in a new P361R-FD mouse model of ACDase deficiency that we generated. P361R-FD mice displayed smaller hearts, altered cardiomyocyte architecture, disrupted tissue composition, and inclusion-containing macrophages. Echocardiography suggested ventricular atrophy, valve dysfunction, decreased cardiac output, and lowered stroke volumes. Troponin I was significantly elevated in P361R-FD mice. Hearts from P361R-FD mice were found to have increased ceramide, cholesterol, and other lipids. Histopathological analysis of heart tissue from neonatal P361R-FD mice revealed lysosomal disruption as early as postnatal day 1. Finally, we report cardiac conduction, striated muscle contraction, and sphingolipid homeostasis gene expression differences during cardiac development in P361R-FD mice. In summary, we investigated the heart in a mouse model of ACDase deficiency, demonstrating that ACDase deficiency induced lysosomal dysfunction, sphingolipid and cholesterol imbalances, tissue disruption, and significant inflammation, leading to impaired cardiac function in these animals.NEW & NOTEWORTHY This is the first characterization of cardiac function and histopathology in a mouse model of acid ceramidase deficiency. We report physiologic disruption suggestive of heart failure with preserved ejection fraction, progressive histopathology, and aberrant gene expression. We found significant lysosomal disruption at both neonatal and adult ages, suggesting a crucial role of acid ceramidase, and potentially ceramides, in cardiac development and function.
Author List
Kleynerman A, Rybova J, McKillop WM, Dlugi TA, Faber ML, Fuller M, O'Meara CC, Medin JAAuthors
Jeffrey A. Medin PhD Professor in the Pediatrics department at Medical College of WisconsinCaitlin C. O'Meara PhD Associate Professor in the Physiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Acid CeramidaseAnimals
Ceramides
Cholesterol
Disease Models, Animal
Farber Lipogranulomatosis
Gene Expression Regulation
Heart Diseases
Lysosomes
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Myocardial Contraction
Myocardium
Myocytes, Cardiac
Sphingolipids
Stroke Volume
Troponin I
