Cardiovascular Dysfunction and Altered Lysosomal Signaling in a Murine Model of Acid Sphingomyelinase Deficiency

TL;DR

This study shows that acid sphingomyelinase deficiency causes heart dysfunction and lysosomal issues in mice, leading to inflammation and fibrosis.

Contribution

This is the first study to characterize baseline cardiac changes in ASMD mice, revealing novel insights into cardiovascular implications of Niemann-Pick Disease.

Findings

ASMD induces lysosomal dysfunction in pericytes and cardiomyocytes, marked by accumulation of lysosomal proteins and autophagosomes.

Cardiac inflammation and fibrosis are observed in Smpd1−/− mice, along with coronary microvascular dysfunction and impaired cardiac function.

Lipid deposition and pericyte-to-myofibroblast transition contribute to interstitial fibrosis in ASMD mice.

Abstract

Niemann-Pick Disease (NPD) is a rare autosomal recessive lysosomal storage disorder (LSD) caused by the deficiency of acid sphingomyelinase (ASMD), which is encoded by the Smpd1 gene. ASMD impacts multiple organ systems in the body, including the cardiovascular system. This study is the first to characterize cardiac pathological changes in ASMD mice under baseline conditions, offering novel insights into the cardiac implications of NPD. Using histological analysis, biochemical assays, and echocardiography, we assessed cardiac pathological changes and function in Smpd1−/− mice compared to Smpd1+/+ littermate controls. Immunofluorescence and biochemical assays demonstrated that ASMD induced lysosomal dysfunction, as evidenced by the accumulation of lysosomal-associated membrane proteins, lysosomal protease, and autophagosomes in pericytes and cardiomyocytes. This lysosomal dysfunction was accompanied by pericytes and cardiomyocytes inflammation, characterized by increased expression of caspase1 and inflammatory cytokines, and infiltration of inflammatory cells in the cardiac tissues of Smpd1−/− mice. In addition, histological analysis revealed increased lipid deposition and cardiac steatosis, along with pericyte-to-myofibroblast transition (PMT) and interstitial fibrosis in Smpd1−/− mice. Moreover, echocardiography further demonstrated that Smpd1−/− mice developed coronary microvascular dysfunction (CMD), as evidenced by decreased coronary blood flow velocity and increased coronary arteriolar wall thickness. Additionally, these mice exhibited significant impairments in systolic and diastolic cardiac function, as shown by a reduced ejection fraction and prolonged left ventricular relaxation time constant (Tau value). These findings suggest that ASMD induces profound pathological changes and vascular dysfunction in the myocardium, potentially driven by mechanisms involving lysosomal dysfunction as well as both pericytes and cardiac inflammation.

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