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. Key messages <UnorderedList Mark="Bullet"> <ItemContent> Lysosomal dysfunction in ASMD leads to impaired autophagic flux in cardiac pericytes </ItemContent> <ItemContent> ASMD causes cardiac inflammation with leukocyte and M2 macrophage infiltration </ItemContent> <ItemContent> Lipid buildup in the pericytes, fibroblasts and myocardium lead to cardiac steatosis </ItemContent> <ItemContent> Enhanced cardiac fibrosis in ASMD links to pericyte-to-myofibroblast transition </ItemContent> <ItemContent> ASMD results in coronary microvascular and diastolic and systolic cardiac dysfunction </ItemContent> </UnorderedList>

Cardiovascular dysfunction and altered lysosomal signaling in a murine model of acid sphingomyelinase deficiency

期刊论文
发表日期：

2025年4月15日

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Yun-Ting Wang,
Alexandra K. Moura,
Rui Zuo,
Kiana Roudbari,
Jenny Z. Hu,
Saher A. Khan,
Zhengchao Wang,
Yangping Shentu,
Mi Wang,
Pin-Lan Li,
Jiukuan Hao,
Yang Zhang,
Xiang Li

摘要

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.

Key messages

Lysosomal dysfunction in ASMD leads to impaired autophagic flux in cardiac pericytes

ASMD causes cardiac inflammation with leukocyte and M2 macrophage infiltration

Lipid buildup in the pericytes, fibroblasts and myocardium lead to cardiac steatosis

Enhanced cardiac fibrosis in ASMD links to pericyte-to-myofibroblast transition

ASMD results in coronary microvascular and diastolic and systolic cardiac dysfunction