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      Autophagy Plays a Critical Role in Klotho Gene Deficiency-induced Arterial Stiffening and Hypertension

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          Abstract

          Objective:

          Klotho is an anti-aging gene that shortens lifespan when disrupted and extends lifespan when overexpressed. This study investigated whether autophagy plays a role in Klotho gene deficiency-induced arterial stiffening and hypertension.

          Methods:

          Klotho mutant heterozygous (KL+/−) mice and age- and sex-matched wild-type (WT) mice were used. Arteries were examined for autophagy using Western blot assays.

          Results:

          Pulse wave velocity (PWV), a direct measure of arterial stiffness, and blood pressure (BP) increased significantly in KL (+/−) mice. The autophagy level, as measured by LC3-II expression and autophagy flux, increased in aortas of KL (+/−) mice, indicating that Klotho gene deficiency upregulated autophagy. Chloroquine diminished Klotho gene deficiency-induced increases in PWV and BP and eliminated the upregulation of autophagic flux in KL (+/−) mice. Klotho gene deficiency-induced arterial stiffness was accompanied by upregulation of MMP9, TGFβ−1, TGFβ−3, RUNX2, and ALP, but these changes were effectively mitigated by chloroquine. Chloroquine also halted an increase in scleraxis expression in aortas of Klotho (+/−) mice. In cultured mouse aortic smooth muscle cells, Klotho gene deficiency increased autophagy, leading to upregulation of scleraxis, a key transcription factor of collagen synthesis. Klotho gene deficiency failed to upregulate scleraxis expression when autophagy was inhibited, suggesting that autophagy is a critical mediator of Klotho gene deficiency-induced upregulation of scleraxis.

          Conclusion:

          Suppression of enhanced autophagy by chloroquine lessens Klotho gene deficiency-induced arterial stiffening and hypertension by stopping upregulation of MMP9 and scleraxis. The enhanced autophagic activity plays a crucial role in Klotho gene deficiency-induced arterial stiffening and hypertension.

          CONDENSED ABSTRACT

          Haplodeficiency of Klotho gene induces autophagy, which is injurious to vasculature and causes arterial stiffening and hypertension. Our study found that suppressing enhanced autophagy by chloroquine diminished arterial stiffness and hypertension in KL+/− mice. Therefore, we suggest that enhanced autophagic activity plays a critical role in the pathogenesis of Klotho deficiency-induced arterial stiffness. Mechanistically, autophagy selectively regulates MMP9 activity, which is necessary for re-organization of collagen by SMCs. Importantly, Klotho deficiency also upregulated expression of scleraxis, an essential transcription factor for collagen synthesis, in an autophagy-dependent manner. Thus, the role of autophagy in Klotho deficiency-induced arterial stiffening and hypertension is mediated through modulation of MMP9 and scleraxis expression.

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          Author and article information

          Journal
          9504370
          8748
          J Mol Med (Berl)
          J. Mol. Med.
          Journal of molecular medicine (Berlin, Germany)
          0946-2716
          1432-1440
          21 October 2019
          19 October 2019
          November 2019
          01 November 2020
          : 97
          : 11
          : 1615-1625
          Affiliations
          [1 ]Department of Physiology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA;
          [2 ]Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
          Author notes

          Authors’ contribution

          Z.S. created the experimental design, provided management for the funding and contributed to writing and editing the manuscript. K.C. executed the experiments, analyzed the data, and contributed to writing the manuscript.

          Address Correspondence and Reprint Requests to: Zhongjie Sun, MD, PhD, FAHA, Professor and Chair, Department of Physiology, University of Tennessee Health Science Center, C302B Coleman Bldg., 956 Court Ave., Memphis, Tennessee, 38163-2116, USA. Tel: 901-448-2679; zsun10@ 123456uthsc.edu
          Article
          PMC7055468 PMC7055468 7055468 nihpa1541296
          10.1007/s00109-019-01841-6
          7055468
          31630227
          0827659c-a6a3-41fd-a1f0-aad4de307b68
          History
          Categories
          Article

          scleraxis,autophagy,arterial stiffness,Beclin-1,hypertension,chloroquine

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