Rationale: The rennin-angiotensin-aldosterone system (RAAS) plays a critical role in the pathogenesis of diabetic cardiomyopathy, but the role of a member of RAAS, angiotensin IV (Ang IV), in this disease and its underlying mechanism are unclear. This study was aimed to clarify the effects of Ang IV and its downstream mediator forkhead box protein O1 (FoxO1) on diabetic cardiomyopathy.

Angiotensin-converting enzyme 2 (ACE2) has proven beneficial in attenuating diabetic cardiomyopathy (DCM) but has been found to be a substrate of a disintegrin and metalloprotease protein-17 (ADAM17). However, whether ADAM17 plays a role in the pathogenesis and intervention of DCM is obscure. In this study, we created cardiomyocyte-specific knockout of ADAM17 (A17^α-MHCKO) mice, and left ventricular dimension, function, pathology and molecular biology were assessed in ADAM17^fl/fl control, A17^α-MHCKO control, ADAM17^fl/fl diabetic and A17^α-MHCKO diabetic mice. Both differentiated H9c2 cells and neonatal rat cardiomyocytes (NRCMs) were used to explore the molecular mechanisms underlying the effect of ADAM17 on DCM. The results showed that protein expression and activity of ADAM17 were upregulated whereas the protein expression of ACE2 was downregulated in the myocardium of diabetic mice. Cardiomyocyte-specific knockout of ADAM17 mitigated cardiac fibrosis and cardiomyocyte apoptosis and ameliorated cardiac dysfunction in mice with DCM. Bioinformatic analyses detected a number of genes enriched in metabolic pathways, in particular the AMPK signaling pathway, expressed differentially between the hearts of A17^α-MHCKO and ADAM17^fl/fl diabetic mice. The mechanism may involve activated AMPK pathway, increased autophagosome formation and improved autophagic flux, which reduced the apoptotic response in cardiomyocytes. In addition, hypoxia-inducible factor-1α (HIF-1α) might act as an upstream mediator of upregulated ADAM17 and ADAM17 might affect AMPK signaling via α1 A-adrenergic receptor (ADRA1A). These results indicated that ADAM17 activity and ACE2 shedding were enhanced in DCM, which was reversed by cardiomyocyte-specific ADAM17 knockout. Thus, inhibition of ADAM17 may provide a promising approach to the treatment of DCM.

After myocardial infarction, the myocardial microenvironment is altered by cardiomyocyte loss, inflammation, and extracellular matrix degradation, creating a hostile environment that severely limits bone marrow‐derived mesenchymal stem cell (BMSC) survival, migration, and differentiation. The BMSCs may differentiate into cardiomyocyte‐like cells in vitro. However, this potential remains significantly limited in vivo because of the lack of supportive signals and conducive microenvironments. To overcome these challenges, this study presents a novel injectable biomimetic microtissue system containing a dual biomimetic extracellular matrix scaffold consisting of Janus Basic Nanotubes, laminin, stromal‐derived factor‐1 alpha, and vascular endothelial growth factor (JLSV) for BMSC delivery (JLSV–BMSC microtissue) designed to mimic the natural myocardial microenvironment. In vitro experiments showed that the microtissue enhanced BMSC survival, proliferation, migration, anti‐apoptotic capacity, and paracrine signaling under oxygen–glucose deprivation conditions. In vivo studies have shown that the microtissue significantly improves BMSC retention at the infarct site, directs their differentiation into cardiomyocytes and endothelial cells, reduces myocardial fibrosis and apoptosis, and promotes angiogenesis, contributing to improved cardiac remodeling and functional recovery. These results suggest that the JLSV–BMSC microtissue is a promising therapeutic strategy for myocardial infarction that addresses the critical challenges of stem cell‐based therapies.

BACKGROUND: The hyperproliferation of smooth muscle cells and deposition of collagen in the pulmonary artery are among the primary characteristics of pulmonary hypertension (PH). These processes contribute to vascular remodeling, ultimately leading to elevated pulmonary artery pressure and right ventricular failure. The MrgD (Mas-related G-protein–coupled receptor member D) exhibits close associations with certain cardiovascular diseases; however, its role in PH remains unclear. METHODS: The effects of the absence or activation of MrgD on PH were investigated using PH animal models induced by Sugen5416+hypoxia, monocrotaline, as well as global or smooth muscle–specific knockout of MrgD. Signaling pathways regulated by MrgD were investigated using high-throughput screening of data from single-cell sequencing of mouse lungs and RNA sequencing of human pulmonary artery smooth muscle cells, as well as other molecular biology experiments. RESULTS: We observed decreased MrgD levels in animal models and patients with PH. Both global and conditional knockout of MrgD exacerbated hypoxia-induced PH in mice. MrgD activation attenuated the PH phenotypes in several established models, although these protective effects were reversed in MrgD-knockout mice. Transcriptome analysis revealed a significantly differentially expressed gene, PIM1 (proviral integration site for Moloney murine leukemia virus 1), as a potential MrgD target. Silencing MrgD increased pulmonary artery smooth muscle cell proliferation by facilitating the AKT (protein kinase B)-mediated interaction of MAZ (MYC-associated Zinc-finger protein) with PIM1 . MrgD activation inhibited this pathway and was ineffective in PH mice with pulmonary artery smooth muscle cells overexpressing PIM1. CONCLUSIONS: MrgD deficiency in pulmonary arterioles increases susceptibility to PH, particularly in a hypoxic environment. MrgD is a potential modeling and therapeutic target for PH.

Background: Qishenyiqi dripping pill for chronic heart failure (CHF) remains controversial due to lack of high-quality trials. Therefore, we conduct this pooled-analysis to evaluate the efficacy and safety of Qishenyiqi in CHF patients. Methods: We searched for randomized clinical trials for Qishenyiqi dripping pill in treating CHF up to August 2018 through China National Knowledge Infrastructure (CNKI), the PubMed Database, the Wanfang Database, the China Scientific Journal Database (VIP), and the Chinese Biomedicine Literature Service System. RevMan 5.3 was used for pooled analyses. Based on the New York Heart Association (NYHA) classification, the clinical therapeutic effect was collected as the primary endpoint. Results: The efficacy and safety of Qishenyiqi combined with routine treatment significantly increased NYHA functional classification, left ventricular ejection fraction, cardiac index, and 6-minute walking test and decreased brain natriuretic peptide, left ventricular end-diastolic, and end-systolic dimensions with no obvious side effects in comparison with routine therapy alone. Conclusions: Together these results provide important insights into Qishenyiqi is effective and safe in improving ventricular remodeling and function of CHF patients. PROSPERO registration number: PROSPERO106695.

Tripartite motif-containing protein 31 (TRIM31), an E3 ubiquitin ligase of the tripartite motif family, plays an important role in the innate immune response. It can reduce the activity of the nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome. However, little information is about glucose metabolic health of TRIM31-deficient mice, and investigations about gut microbiota in TRIM31-deficient mice is limited. Thus, we aimed to compare glucose metabolic parameters, gut microbiota composition and inflammatory cytokine levels between TRIM31^−/− and wild-type (WT) mice, and further investigate whether or not certain gut microbiota taxon correlates with specific metabolic parameters and inflammation cytokines in TRIM31-deficient mice. TRIM31^−/− mice showed glucose intolerance and insulin resistance, with a significant difference in gut microbiota composition, characterized by increased abundance of Prevotellaceae and Veillonellaceae. TRIM31^−/− mice with impaired glucose metabolism was accompanied by elevated serum tumor necrosis factor-α (TNF-α) and interleukin 1β (IL-1β) concentrations, as well as upregulated caecal TNF-α, IL-1β, caspase-1, and NLRP3 expressions. Furthermore, elevated p-IRS-1/IRS-1 protein expression, and decreased Akt Thr308 phosphorylation were observed in TRIM31^−/− mice. Prevotellaceae abundance was positively associated with caecal IL-1β mRNA expression, and Veillonellaceae was associated with higher TNF-α mRNA expression and serum insulin concentration. In conclusion, our study is novel in showing that TRIM31 deficiency is associated with impaired glucose metabolism and disrupted gut microbiota in mice. This study contributes to the theoretical foundation on the potential relationship between TRIM31 deficiency and the development of abnormal glucose metabolism.