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 Herpud1 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 Herpud1 in the Hcy-related osteogenic differentiation of AVICs was investigated by manipulating of Herpud1 expression. RESULTS: Herpud1 was highly expressed in calcified human and mouse aortic valves as well as primary aortic valve interstitial cells (AVICs). Hcy increased Herpud1 expression through the ERS pathway and promoted CAVD progression. Herpud1 deficiency inhibited hcy-induced CAVD in vitro and in vivo. Herpud1 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 Herpud1 biosynthesis. CONCLUSIONS: These findings identify a previously unknown mechanism of Herpud1 upregulation in Hcy-related CAVD, suggesting that Herpud1 silencing or inhibition is a viable therapeutic strategy for arresting CAVD progression. HIGHLIGHTS: • Herpud1 is upregulated in the leaflets of Hcy-treated mice and patients with CAVD. • In mice, global knockout of Herpud1 alleviates aortic valve calcification and Herpud1 silencing activates cell autophagy, inhibiting osteogenic differentiation of AVICs induced by Hcy. • 4-PBA suppressed Herpud1 expression to alleviate AVIC calcification in Hcy treated AVICs and to mitigate aortic valve calcification in mice.

A Nomogram for Predicting Patent Foramen Ovale-Related Stroke Recurrence.

Background: The high prevalence of patent foramen ovale (PFO) in cryptogenic stroke suggested a stroke-causing role for PFO. As risk factors for recurrence of such stroke are not recognized, clinicians cannot sufficiently identify, treat, and follow-up high-risk patients. Therefore, this study aimed to establish a prediction model for PFO-related stroke recurrence. Methods: This study included 392 patients with PFO-related stroke in a training set and 164 patients with PFO-related stroke in an independent validation set. In the training set, independent risk factors for recurrence identified using forward stepwise Cox regression were included in nomogram 1, and those identified using least absolute shrinkage and selection operator(LASSO)regression were included in nomogram 2. Nomogram performance and discrimination were assessed using the concordance index (C-index), area under the curve (AUC), calibration curve, and decision curve analyses (DCA). The results were also validated in the validation set. Results: Nomogram 1 was based on homocysteine (Hcy), high-sensitivity C-reactive protein (hsCRP), and albumin (ALB), and nomogram 2 was based on age, diabetes, hypertension, right-to-left shunt, ALB, prealbumin, hsCRP, and Hcy. The C-index of nomogram 1 was 0.861, which was not significantly different from that of nomogram 2 (0.893). The 2- and 5-year AUCs of nomogram 1 were 0.863 and 0.777, respectively. In the validation set, nomogram 1 still had good discrimination (C-index, 0.862; 2-year AUC, 0.839; 5-year AUC, 0.990). The calibration curve showed good homogeneity between the prediction by nomogram 1 and the actual observation. DCA demonstrated that nomogram 1 was clinically useful. Moreover, patients were successfully divided into two distinct risk groups (low and high risk) for recurrence rate by nomogram 1. Conclusions: Nomogram 1, based on Hcy, hsCRP, and ALB levels, provided a more clinically realistic prognostic prediction for patients with PFO-related stroke. This model could help patients with PFO-related stroke to facilitate personalized prognostic evaluations.

Functional components of Chinese rice wine can ameliorate diabetic cardiomyopathy through the modulation of autophagy, apoptosis, gut microbiota, and metabolites.

Background: Dietary polyphenols, polypeptides, and oligosaccharides modulate inflammation and immunity by altering the composition of gut microbiota. The polyphenols and polypeptides in Chinese rice wine have protective effects against cardiovascular disease. In this study, we hypothesized that the polyphenols, polypeptides, and oligosaccharides in Chinese rice wine can ameliorate diabetic cardiomyopathy (DCM) by altering gut microbiota and metabolites. Methods: Mice with DCM and high glucose cells were treated with rice wine polyphenols (RWPH), rice wine polypeptides (RWPE), and rice wine oligosaccharides. Cardiac function was evaluated by echocardiography and detection of myocardial injury markers. We observed the pathological structures using hematoxylin and eosin staining, Masson's trichrome staining, and transmission electron microscopy. The expression levels of autophagy-related proteins and stubRFP-sensGFP-LC3 fluorescence were measured to evaluate autophagy. We performed TUNEL staining and measured the levels of Bax, Bcl-2, and p53 to assess apoptosis. To analyze the effects of the rice wine functional components on the gut microbiota and metabolites of DCM mice, we performed fecal 16S-rDNA gene sequencing and serum untargeted metabolomics. Results: Our results showed an increase in cardiac and mitochondrial function, promotion of autophagy, and inhibition of cardiomyocyte apoptosis, which indicates that RWPH and RWPE can ameliorate DCM. The abundance of Akkermansia and Desulfovibrio were reduced by the presence of RWPH and RWPE. The growth of the Lachnospiraceae_NK4A136_group and Clostridiales-unclassified were promoted by the presence of RWPH. Tryptophan metabolism-associated metabolites were increased and phenylalanine levels were reduced by the presence of RWPH and RWPE. The biosynthesis of primary bile acids was enhanced by the presence of RWPH. Conclusion: Both RWPH and RWPE provided a protective effect against DCM by promoting autophagy, inhibiting apoptosis, and reversing both gut microbiota dysbiosis and metabolic dysregulation.