Herpud1 deficiency alleviates homocysteine-induced aortic valve calcification

Abstract

Objectives: To evaluate the role and therapeutic value of homocysteine (hcy)-inducible endoplasmic reticulum stress (ERS) protein with ubiquitin like domain 1 (Herpud1) in hcy-induced calci c aortic valve disease (CAVD).Background: The morbidity and mortality rates of calci c aortic valve disease (CAVD) remain high while treatment options are limited.Methods: In vivo , we use the low-density lipoprotein receptor (LDLR) and Herpud1 double knockout (LDLR-/-/Herpud1-/-) mice assessment of aortic valve calci cation lesions, ERS activation, autophagy, and osteogenic differentiation of aortic valve interstitial cells (AVICs). We used siRNA to knock down Herpud1 in cultured Primary AVICs were isolated from mice to further validate our ndings.Results: Herpud1 was highly expressed in calci ed human and mouse aortic valves as well as primary aortic valve interstitial cells (AVICs). Herpud1 de ciency inhibited hcy-induced CAVD in vitro and in vivo.Herpud1 silencing activated cell autophagy, which subsequently inhibited hcy-induced osteogenic differentiation of AVICs. Hcy increased Herpud1 expression through the ERS pathway and promoted CAVD progression. ERS inhibitor 4-phenyl butyric acid (4-PBA) signi cantly attenuated aortic valve calci cation in high methionine diet-fed low-density lipoprotein receptor -/-(LDLR -/-) mice by suppressing ERS and subsequent Herpud1 biosynthesis.Conclusions: These ndings identify a previously unknown mechanism of Herpud1 upregulation in CAVD progression, suggesting that Herpud1 silencing or inhibition is a viable therapeutic strategy for arresting CAVD progression. HighlightsHomocysteine (hcy) promotes aortic valvular calci cation in vivo and in vitro.Herpud1 is upregulated in the lea ets of mice and humans with CAVD. Herpud1 de ciency inhibited hcy-induced CAVD in vitro and in vivo.Herpud1 silencing activates cell autophagy, inhibiting osteogenic differentiation of primary aortic valve interstitial cells (AVICs) induced by hcy. 4-Phenyl butyric acid, a compound that suppresses ERS and subsequent Herpud1 biosynthesis, signi cantly decreased AVIC calci cation in vitro after hcy stimulation and mitigated the severity of aortic valve brosis and calci cation in a murine model of CAVD.

Investigation of autophagy‑related genes and immune infiltration in calcific aortic valve disease: A bioinformatics analysis and experimental validation

“…Although numerous of the factors contributing to valve calcification are understood, the role of autophagy within this process remains elusive ( 18 , 34 ). This significant research gap warrants further investigation.…”

Valsartan Attenuated Homocysteine-Induced Impaired Autophagy and ER Stress in Human Umbilical Vein Endothelial Cells

“…As such, mTOR suppression by some chemicals (e.g., rapamycin) stimulates autophagy. Hcy has been found to inhibit autophagy through mTOR in neurons [ 30 ] and aortic valve interstitial cells [ 31 ]. GSK-3 β is involved in the regulation of autophagy.…”