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Aging impairs arterial compliance via Klotho-mediated downregulation of B-cell population and IgG levels

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Abstract

Objective

Aging is associated with compromised immune function and arterial remodeling and stiffness. The purpose of this study is to investigate whether in vivo AAV-based delivery of secreted Klotho (SKL) gene (AAV-SKL) improves aging- and senescence-associated immune dysfunction and arterial stiffness.

Methods and results

Senescence-accelerated mice prone strain 1 (SAMP1, 10 months) and old mice (20 months) were used. Serum SKL levels, B-cell population and serum IgG levels were markedly decreased in SAMP1 and old mice. Rescue of downregulation of serum SKL levels by in vivo AAV2-based delivery of SKL gene (AAV-SKL) increased B-cell population and serum IgG levels and attenuated arterial stiffness in SAMP1 and old mice. Thus, Klotho deficiency may play a role in senescence- and aging-associated humoral immune dysfunction and arterial stiffness. Vascular infiltration of inflammatory cells and expression of TGFβ1, collagen 1, scleraxis, MMP-2 and MMP-9 were increased while the elastin level was decreased in aortas of SAMP1 and old mice which can be rescued by AAV-SKL. Interestingly, treatment with IgG effectively rescued arterial inflammation and remodeling and attenuated arterial stiffness and hypertension in aging mice. In cultured B-lymphoblast cells, we further showed that SKL regulates B-cell proliferation and maturation partly via the NFkB pathway.

Conclusion

Aging-associated arterial stiffening may be largely attributed to downregulation of B-cell population and serum IgG levels. AAV-SKL attenuates arterial stiffness in aging mice partly via restoring B-cell population and serum IgG levels which attenuates aging-associated vascular inflammation and arterial remodeling.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by NIH R01 AG062375, AG049780, HL118558, and HL154147.

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Authors and Affiliations

  1. Department of Physiology, College of Medicine, University of Oklahoma Health Science Center, Oklahoma City, OK, USA

    Jun Fan, Shirley Wang, Kai Chen & Zhongjie Sun

  2. Department of Physiology, College of Medicine, University of Tennessee Health Science Center, A302 Coleman Building, 956 Court Avenue, Memphis, TN, 38163, USA

    Kai Chen & Zhongjie Sun

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  1. Jun Fan
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  2. Shirley Wang
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Contributions

Zhongjie Sun contributed to the study conception and design. Material preparation, data collection and analysis were performed by Jun Fan, Shirley Wang and Kai Chen. The first draft of the manuscript was written by Jun Fan and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Zhongjie Sun.

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The authors have no conflict of interest to declare. The authors declare no competing financial interests.

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This study was carried out according to the Guidelines of the National Institutes of Health on the Care and Use of Laboratory Animals. The study complies with the Declaration of Helsinki. This project was approved by Institutional Animal Care and Use Committee (IACUC) of the University of Oklahoma Health Sciences Center.

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Current address of Jun Fan: Department of Tissue Engineering, School of Intelligent Medicine, China Medical University, Shenyang, 110122, China.

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Fan, J., Wang, S., Chen, K. et al. Aging impairs arterial compliance via Klotho-mediated downregulation of B-cell population and IgG levels. Cell. Mol. Life Sci. 79, 494 (2022). https://doi.org/10.1007/s00018-022-04512-x

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