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Chloroquine Attenuates Klotho Gene Deficiency‐induced Arterial Stiffening and Hypertension by Suppression of Autophagy
Author(s) -
Chen Kai,
Sun Zhongjie
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1206.12
Subject(s) - autophagy , klotho , downregulation and upregulation , chloroquine , gene knockdown , endocrinology , medicine , arterial stiffness , chemistry , biology , kidney , blood pressure , immunology , gene , apoptosis , biochemistry , malaria
Background & Hypothesis Hapodeficiency of the antiaging gene Klotho causes arterial stiffening and hypertension through unknown mechanisms. Our recent study showed that autophagy was upregulated in the aortas of Klotho mutant heterozygous (+/−) mice. We hypothesized that inhibition of autophagy by chloroquine (an anti‐malaria drug) attenuates Klotho deficiency‐induced arterial stiffening and hypertension. Methods & Results Klotho mutant heterozygous (+/−) mice and age‐ and sex‐matched wild‐type (WT) mice were used (20–23 months). Pulse wave velocity (PWV), a direct measure of arterial stiffness, and blood pressure (BP) were increased significantly in KL(+/−) mice. Interestingly, inhibition of autophagy by chloroquine reversed Klotho deficiency‐induced increases in PWV and BP within 2 weeks of treatment. The autophagy level, as measured by LC3I/LC3II and autophagy flux, was increased in aortas of KL(+/−) mice. Chloroquine abolished the upregulation of autophagy in Klotho (+/−) mice, indicating effective inhibition of autophagy. Klotho deficiency‐induced arterial stiffness was associated with accumulation of stiffer collagen and degeneration of compliant elastin fibers. In addition, the activity and expression of MMP2, MMP9, and the expression of TGF‐β1, TGF‐β3, RUNX2 and ALP were increased in aortas of KL(+/−) mice, which were attenuated by chloroquine. Scleraxis, a transcription factor in the regulation of collagen synthesis in arterial cells, was increased in aortas of KL( +/− ) mice. The upregulation of scleraxis by Klotho deficiency was eliminated by inhibition of autophagy, which was further confirmed by inhibition of autophagy through siRNA knockdown of Beclin‐1 in mouse vascular aortic smooth muscle cells. Therefore, induction of autophagy is essential for Klotho deficiency–induced upregulation of scleraxis. Conclusion Klotho gene deficiency causes arterial stiffening and hypertension through upregulation of scleraxis in an autophagy‐dependent manner. Support or Funding Information Supported by NIH R01 HL118558, DK093403, HL105302 and HL102074.