SIRT6-mediated Runx2 downregulation inhibits osteogenic differentiation of human aortic valve interstitial cells in calcific aortic valve disease.

Calcific aortic valve disease (CAVD) is a progressive cardiovascular disorder involving multiple pathogenesis. Effective pharmacological therapies are currently unavailable. Sirtuin6 (SIRT6) has been shown to protect against aortic valve calcification in CAVD. The exact regulatory mechanism of SIRT6 in osteoblastic differentiation remains to be determined, although it inhibits osteogenic differentiation of aortic valve interstitial cells. We demonstrated that SIRT6 was markedly downregulated in calcific human aortic valves. Mechanistically, SIRT6 suppressed osteogenic differentiation in human aortic valve interstitial cells (HAVICs), as confirmed by loss- and gain-of-function experiments. SIRT6 directly interacted with Runx2, decreased Runx2 acetylation levels, and facilitated Runx2 nuclear export to inhibit the osteoblastic phenotype transition of HAVICs. In addition, the AKT signaling pathway acted upstream of SIRT6. Together, these findings elucidate that SIRT6-mediated Runx2 downregulation inhibits aortic valve calcification and provide novel insights into therapeutic strategies for CAVD.

Celastrol confers ferroptosis resistance via AKT/GSK3ß signaling in high-fat diet-induced cardiac injury.

Obesity-induced cardiac dysfunction is a severe global disease associated with high dietary fat intake, and its pathogenesis includes inflammation, oxidative stress, and ferroptosis. Celastrol (Cel) is a bioactive compound isolated from the herb Tripterygium wilfordii, which has a protective influence on cardiovascular diseases. In this study, the role of Cel in obesity-induced ferroptosis and cardiac injury was investigated. We found that Cel alleviated ferroptosis induced by Palmitic acid (PA), exhibiting a decrease in the LDH, CK-MB, Ptgs2, and Lipid Peroxidation levels. After cardiomyocytes were treated with additional LY294002 and LiCl, Cel exerted its protective effect through increased AKT/GSK3ß phosphorylation and decreased level of lipid peroxidation and Mitochondrial ROS. The systolic left ventricle (LV) dysfunction of obese mice was alleviated via ferroptosis inhibition by elevated p-GSK3ß and decreased Mitochondrial ROS under Cel treatment. Moreover, mitochondrial anomalies included swelling and distortion in the myocardium which was relieved with Cel. In conclusion, our results demonstrate that ferroptosis resistance with Cel under HFD conditions targets AKT/GSK3ß signaling, which provides novel therapeutic strategies in obesity-induced cardiac injury.

Corrigendum: Clinical outcomes following surgical mitral valve plasty or replacement in patients with infectious endocarditis: A meta-analysis.

[This corrects the article DOI: 10.3389/fsurg.2022.1048036.].

Adipose tissue macrophage-derived exosomes induce ferroptosis via glutathione synthesis inhibition by targeting SLC7A11 in obesity-induced cardiac injury.

Ferroptosis is an iron-dependent programmed cell death characterized by the accumulation of reactive oxygen species (ROS). Long-term high fat diet (HFD) was found to be associated with ferroptosis and cardiac injury. HFD-induced obesity is characterized by sustained, low-grade inflammation in adipose tissue, while macrophage infiltration plays a crucial role in inflammation. Exosomes (Exos) derived from adipose tissue macrophages (ATMs) participate in the physiological processes of recipient cells. In this study, we investigated the role of ATM-Exos in obesity-induced ferroptosis and cardiac injury. We found that HFD-induced obesity resulted in higher mRNA expression levels of specific markers, e.g., prostaglandin endoperoxide synthase 2 (PTGS2), and increased the levels of lipid peroxides, including malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). Macrophages infiltrated the adipose tissues, as examined by flow cytometry. Exosomes derived from ATM-Exos were analyzed using transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Obese ATM-Exos administration induced higher levels of PTGS2, MDA, 4-HNE, lipid ROS, and mitochondrial injury. Obese ATM-Exos further provoked obvious cardiac injury, demonstrated by abnormal levels of cardiac enzymes and inflammatory factors. Systolic left ventricle (LV) function anomalies were induced by ATM-Exos in obese mice. miR-140-5p is abundant in obese ATM-Exos and promotes ferroptosis in cardiomyocytes. Solute carrier family 7 member 11 (SLC7A11) is a downstream target of miR-140-5p, which induces ferroptosis via inhibition of GSH synthesis by targeting SLC7A11. Attenuating exosomal-miR-140-5p expression alleviates ferroptosis and cardiac injury induced by obese ATM exosomes by alleviating GSH inhibition. In summary, the current study provides evidence that obese ATM-exosomal miR-140-5p promotes ferroptosis by regulating GSH synthesis and provides a novel therapeutic strategy for targeting obese ATM-Exos in obesity-induced cardiac injury.

Transcription factor Sp2 promotes TGFB-mediated interstitial cell osteogenic differentiation in bicuspid aortic valves through a SMAD-dependent pathway.

Calcification of the bicuspid aortic valve (BAV) involves differential expression of various RNA genes, which is achieved through complex regulatory networks that are controlled in part by transcription factors and microRNAs. We previously found that miR-195-5p regulates the osteogenic differentiation of valvular interstitial cells (VICs) by targeting the TGF-ß pathway. However, the transcriptional regulation of miR-195-5p in calcified BAV patients is not yet clear. In this study, stenotic aortic valve tissues from patients with BAVs and tricuspid aortic valves (TAVs) were collected. Candidate transcription factors of miR-195-5p were predicted by bioinformatics analysis and tested in diseased valves and in male porcine VICs. SP2 gene expression and the corresponding protein levels in BAV were significantly lower than those in TAV, and a low SP2 expression level environment in VICs resulted in remarkable increases in RNA expression levels of RUNX2, BMP2, collagen 1, MMP2, and MMP9 and the corresponding proteins. ChIP assays revealed that SP2 directly bound to the transcription promoter region of miR-195-5p. Cotransfection of SP2 shRNA and a miR-195-5p mimic in porcine VICs demonstrated that SP2 repressed SMAD7 expression via miR-195-5p, while knockdown of SP2 increased the mRNA expression of SMAD7 and the corresponding protein and attenuated Smad 2/3 expression. Immunofluorescence staining of diseased valves confirmed that the functional proteins of osteogenesis differentiation, including RUNX2, BMP2, collagen 1, and osteocalcin, were overexpressed in BAVs. In Conclusion, the transcription factor Sp2 is expressed at low levels in VICs from BAV patients, which has a negative impact on miR-195-5p expression by binding its promoter region and partially promotes calcification through a SMAD-dependent pathway.

Clinical outcomes following surgical mitral valve plasty or replacement in patients with infectious endocarditis: A meta-analysis.

Background: For degenerative mitral disease, more and more evidences support that mitral valve plasty (MVP) has much better clincial outcomes than mitral valve replacement (MVR). However, the advantages of MVP in patients suffering from infectious endocarditis (IE) are unclear. To evaluate the appropriateness of MVP in IE patients, we conducted this meta-analysis. Based on the difference between active and healed phase, we not only compared the result of patients with IE, but also identified the subgroup with active IE. Methods: We systematically searched the clinical trials comparing clinical outcomes of MVP and MVR in patients suffering from IE. Relevant articles were searched from January 1, 2000 to March 18, 2021 in Pubmed and Cochrane Library. Studies were excluded if they were with Newcastle-Ottawa Scale (NOS) score less than 6 or lacking of direct comparisons between MVP and MVR. Results: 23 studies were involved and 25,615 patients were included. Pooled analysis showed fewer adverse events and early or long-term death in the MVP group. However, more reoperations existed in this patient group. And the reinfection rate was close between two groups. Similar results were observed after identifying active IE subgroup, but there is no difference in the freedom from reoperation due to all-events. Conclusions: Although limitimations exited in this study, patients suffering from IE can benefit from both MVP and MVR. For surgeons with consummate skills, MVP can be the preferred choice for suitable IE patients.