| First Author | Chen K | Year | 2019 |
| Journal | J Mol Med (Berl) | Volume | 97 |
| Issue | 11 | Pages | 1615-1625 |
| PubMed ID | 31630227 | Mgi Jnum | J:324734 |
| Mgi Id | MGI:7281430 | Doi | 10.1007/s00109-019-01841-6 |
| Citation | Chen K, et al. (2019) Autophagy plays a critical role in Klotho gene deficiency-induced arterial stiffening and hypertension. J Mol Med (Berl) 97(11):1615-1625 |
| abstractText | Klotho is an anti-aging gene that shortens the life span when disrupted and extends the lifespan when overexpressed. This study investigated whether autophagy plays a role in Klotho gene deficiency-induced arterial stiffening and hypertension. 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. 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, TGFbeta-1, TGFbeta-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. 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. KEY MESSAGES: Klotho gene deficiency upregulates autophagy. Upregulation of autophagy plays a role in the pathogenesis of arterial stiffening. Autophagy regulates MMP9 activity and scleraxis expression. |
