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Deficiency of NONO is associated with impaired cardiac function and fibrosis in mice
Xingli Xu1, Hong Jiang1, Yue Lu1
1The Key Laboratory of Cardiovascular Remodeling and Function Researcdh, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
Abstract:
Non-POU-domain-containing octamer-binding protein (NONO), a component of multifunctional Drosophila behavior/human splicing (DBHS) family, plays an important role in regulating glucose and fat metabolism, circadian cycles, cell division, collagen formation and fibrosis. Dysfunctional variants of NONO have been described as the cause of congenital heart defects in males. However, the effects of NONO deficiency on the ventricular function and cardiac fibrosis as well as the related mechanisms are not clear. In the present study, we aimed to reveal the overall phenotypes, cardiac function and fibroblasts in NONO knockout (NONO KO) mice compared with the wild-type (WT) male littermates. The results showed that the birth rate of NONOgt/0 mice was much lower than their WT male littermates at the time of weaning. The body weight of NONOgt/0 mice was 19% lower than that of WT male littermates (27.2 ± 1.49 g vs. 22.01 ± 1.20 g, P < .001). NONO KO mice exhibited continuous higher mortality from birth to a year later (P < .05). Compared with those in the WT mice, the heart weight was lower(142.0 ± 8.7 mg vs. 179.0 ± 10.4 mg, P < .001), the heart weight to body weight ratio (HW/BW) was similar, the E/A ratio was higher (1.80 ± 0.47 vs. 1.44 ± 0.26, P < .05), and the left ventricular end diastolic diameter (LVEDd) was significantly lower (2.72 ± 0.51 mm vs.3.54 ± 0.43 mm, P < .001) in the NONO KO mice. We also found excessive matrix deposition in vivo. In vitro, NONO deficiency led to fibroblasts hyperproliferation, while migration was inhibited, which would induce collagen maturation and deposition. Conversely, overexpression of NONO inhibited fibroblasts proliferation and increased migration which reduced collagen deposition. RNA-seq of cardiac fibroblasts further indicated that NONO deficiency upregulated the cell cycle regulators, which included cyclin B2, the origin recognition complex 1 (ORC1) and cell division cycle 6 (CDC6), while downregulated the migration regulators, which included myosins, integrin and coagulation factor II. Overexpression of NONO further verified the effects of these indicators. In conclusion, our study demonstrated that NONO deficiency was associated with developing heart defects in mice. Hyperproliferation of cardiac fibroblasts with dramatically excessive collagen secretion might be the cause of heart defects of NONO KO mice.
Insights
Non-POU-domain-containing octamer-binding protein (NONO) deficiency in mice leads to heart defects, characterized by increased cardiac fibroblast proliferation and excessive collagen deposition. This highlights NONO
Area of Science:
- Cardiovascular Biology
- Molecular Genetics
- Cellular Physiology
Background:
- Non-POU-domain-containing octamer-binding protein (NONO) is a multifunctional protein involved in metabolism, cell division, and fibrosis.
- NONO variants are linked to congenital heart defects, but its role in ventricular function and cardiac fibrosis remains unclear.
Purpose of the Study:
- To investigate the effects of NONO deficiency on cardiac function, ventricular remodeling, and fibroblast behavior in NONO knockout (NONO KO) mice.
- To elucidate the molecular mechanisms underlying NONO's role in cardiac fibrosis and heart development.
Main Methods:
- Phenotypic analysis of NONO KO mice, including survival rates, body weight, and cardiac measurements (heart weight, heart weight to body weight ratio, E/A ratio, left ventricular end diastolic diameter).
- In vivo assessment of matrix deposition and in vitro studies on cardiac fibroblast proliferation and migration.
- RNA-sequencing (RNA-seq) analysis of cardiac fibroblasts to identify dysregulated genes in NONO-deficient cells.
Main Results:
- NONO KO mice exhibited reduced birth rates, lower body weight, and increased mortality.
- Cardiac analysis revealed lower heart weight, higher E/A ratio, and significantly reduced left ventricular end diastolic diameter in NONO KO mice.
- NONO deficiency led to excessive matrix deposition, hyperproliferation of cardiac fibroblasts, inhibited migration, and altered expression of cell cycle and migration regulators.
Conclusions:
- NONO deficiency is associated with the development of heart defects in mice.
- Hyperproliferation and excessive collagen secretion by cardiac fibroblasts due to NONO deficiency are likely mechanisms causing heart defects.
- NONO plays a critical role in maintaining cardiac homeostasis and fibroblast function.
