Herpud1 deficiency alleviates homocysteine-induced aortic valve calcification

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 calcific aortic valve disease (CAVD).Background The morbidity and mortality rates of calcific aortic valve disease (CAVD) remain high while treatment options are limited.Methods In vivo, we use the low-density lipoprotein receptor (LDLR) and Her pud1 double knockout (LDLR-/-/Herpud1-/-) mice and used high methionine diet (HMD) to assess of aortic valve calcification lesions, ERS activation, autophagy, and osteogenic differentiation of aortic valve interstitial cells (AVICs). In vitro, the role of Her pud1 in the Hcy-related osteogenic differentiation of AVICs was investigated by manipulating of Her pud1 expression.Results Her pud1 was highly expressed in calcified human and mouse aortic valves as well as primary aortic valve interstitial cells (AVICs). Hcy increased Her pud1 expression through the ERS pathway and promoted CAVD progression. Her pud1 deficiency inhibited hcy-induced CAVD in vitro and in vivo. Her pud1 silencing activated cell autophagy, which subsequently inhibited hcy-induced osteogenic differentiation of AVICs. ERS inhibitor 4-phenyl butyric acid (4-PBA) significantly attenuated aortic valve calcification in HMD-fed low-density lipoprotein receptor-/- (LDLR-/-) mice by suppressing ERS and subsequent Her pud1 biosynthesis.Conclusions These findings identify a previously unknown mechanism of Her pud1 upregulation in Hcy-related CAVD, suggesting that Her pud1 silencing or inhibition is a viable therapeutic strategy for arresting CAVD progression.Highlights center dot Herpud1 is upregulated in the leaflets of Hcy-treated mice and patients with CAVD.center dot In mice, global knockout of Her pud1 alleviates aortic valve calcification and Her pud1 silencing activates cell autophagy, inhibiting osteogenic differentiation of AVICs induced by Hcy.center dot 4-PBA suppressed Her pud1 expression to alleviate AVIC calcification in Hcy treated AVICs and to mitigate aortic valve calcification in mice.

Automated summary

The study reveals the important role and therapeutic value of Homocysteine-inducible Endoplasmic Reticulum Stress Protein with Ubiquitin Like Domain 1 (Herpud1) in Homocysteine-induced Calcific Aortic Valve Disease (CAVD). It is found that Herpud1 deficiency inhibits the development of CAVD induced by homocysteine and activates cell autophagy to inhibit the osteogenic differentiation of AVICs. Moreover, inhibiting endoplasmic reticulum stress and Herpud1 biosynthesis can alleviate AVIC calcification induced by homocysteine and mitigate aortic valve calcification.