Background: Relaxin (RLX) can prevent cardiac fibrosis. We aimed to investigate the possible mechanism and signal transduction pathway of RLX inhibiting cardiac fibrosis. Methods: Isoproterenol (5 mg·kg^-1·d^-1) was used to establish the cardiac fibrosis model in rats, which were administered RLX. The cardiac function, related targets of cardiac fibrosis, and endothelial–mesenchymal transition (EndMT) were measured. Transforming growth factor β (TGF-β) was used to induce EndMT in human umbilical vein endothelial cells, which were pretreated with RLX, 200 ng·mL^-1, then with the inhibitor of Notch. Transwell cell migration was used to evaluate cell migration. CD31 and vimentin content was determined by immunofluorescence staining and Western blot analysis. Notch protein level was examined by Western blot analysis. Results: RLX improved cardiac function in rats with cardiac fibrosis; it reduced the content of collagen I and III, increased the microvascular density of the myocardium, and suppressed the EndMT in heart tissue. In vitro, RLX decreased the mobility of human umbilical vein endothelial cells induced by TGF-β, increased the expression of endothelial CD31, and decreased vimentin content. Compared to TGF-β and RLX co-culture alone, TGF-β + RLX + Notch inhibitor increased cell mobility and the EndMT, but decreased the levels of Notch-1, HES-1, and Jagged-1 proteins. Conclusion: RLX may inhibit the cardiac fibrosis via EndMT by Notch-mediated signaling.

Scutellarin (SCU) is the major active component of breviscapine and has been reported to be capable of decreasing myocardial fibrosis. The aim of the present study is to investigate whether SCU treatment attenuates isoprenaline-induced myocardial fibrosis and the mechanisms of its action. Rats were injected subcutaneously with isoprenaline (Iso) to induce myocardial fibrosis and rats in the SCU treatment groups were intraperitoneally infused with SCU (10 mg·kg⁻¹·d⁻¹ or 20 mg·kg⁻¹·d⁻¹, for 14 days). Post-treatment, cardiac functional measurements and the left and right ventricular weight indices (LVWI and RVWI, respectively) were analysed. Pathological alteration, expression of type I and III collagen, Von Willebrand factor, α-smooth muscle actin, cluster of differentiation-31 (CD31), and the Notch signalling proteins (Notch1, Jagged1 and Hes1) were examined. The administration of SCU resulted in a significant improvement in cardiac function and decrease in the cardiac weight indices; reduced fibrous tissue proliferation; reduced levels of type I and III collagen; increased microvascular density; and decreased expression of α-smooth muscle actin and increased expression of CD31, Notch1, Jagged1 and Hes1 in isoprenaline-induced myocardial fibrosis in rats. Our results suggest that SCU prevents isoprenaline-induced myocardial fibrosis via inhibition of cardiac endothelial-mesenchymal transition potentially, which may be associated with the Notch pathway.

Background: The systemic immune-inflammation index (SII; neutrophil × platelet/lymphocyte) is a novel marker for immune and inflammatory status and is associated with adverse prognosis in cardiovascular disease. Methods: In total, 744 patients diagnosed with acute coronary syndrome (ACS) and chronic kidney disease (CKD) were included in our study, received standard therapies, and were followed up. Patients were divided into high and low SII groups according to the baseline SII. The primary endpoint was major cardiovascular events (MACEs), defined as cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. Results: During a median follow-up of 2.5 years, a total of 185 (24.9%) MACEs were recorded. Analysis of the ROC curve revealed that the best cutoff value of SII was 1159.84× 10⁹/L for predicting MACEs. The Kaplan–Meier analysis showed that those patients in the low SII group had higher survival rates than those in the high SII group (p < 0.001). Compared to those in the low SII group, patients in the high SII group were at significantly higher risk of MACEs (134 (38.8%) vs 51 (12.8%), p < 0.001). Univariate and multivariable Cox regression analyses revealed that a high SII level was independently associated with MACEs in ACS patients with CKD (adjusted hazard ratio [HR]: 1.865, 95% confidence interval [CI]: 1.197– 2.907, p = 0.006). Conclusion: The present study showed that an elevated SII is associated with adverse cardiovascular outcomes in ACS with CKD patients, suggesting that SII may be a valuable predictor of poor prognosis in ACS with CKD patients. Further studies are needed to confirm our findings.

Background: Fibrosis results in excessive buildup of extracellular matrix proteins along with abnormalities in structure and is partly derived by a process involving transforming growth factor β (TGF-β) called endothelial-to-mesenchymal transition (EndMT). We investigated whether the aldosterone receptor-blocker spironolactone could abrogate TGF-β-induced fibrosis in EndMT and the underlying mechanism. Methods: Human umbilical vein endothelial cells (HUVECs) were divided into 5 groups for treatment: blank; vehicle control; TGF-β (10 ng/ml); spironolactone (1 μM)+TGF-β; and spironolactone+TGF-β+DAPT (10 μM). Cell chemotaxis was assayed by transwell assay. The expression of CD31 and vimentin was determined by Immunofluorescence staining and western blot analysis. Notch1 protein level was detected by western blot analysis. Results: Spironolactone significantly prevented TGF-β-stimulated EndMT by down-regulate vimentin and up-regulate CD31 in HUVECs (p<0.01).It inhibited cell migration during EndMT (p<0.01). The protective effect of spironolactone against EndMT could be attenuated by blocking the Notch signal pathway with DAPT (p<0.01). Notch signaling was activated and cross-interacted with TGF-β and spironolactone in regulating EndMT in HUVECs and reversed the spironolactone-related signaling by abrogating the antifibrotic actions with decreased Notch1 protein expression (p<0.01). Conclusion: Spironolactone may have a protective role in TGF-β-induced EndMT in HUVECs mediated by the Notch signal pathway.

Background: Familial hypercholesterolemia (FH) is an inherited metabolic disorder with a high level of low-density lipoprotein cholesterol and the worse prognosis. The triglyceride-glucose (TyG) index, an emerging tool to reflect insulin resistance (IR), is positively associated with a higher risk of atherosclerotic cardiovascular disease (ASCVD) in healthy individuals, but the value of TyG index has never been evaluated in FH patients. This study aimed to determine the association between the TyG index and glucose metabolic indicators, insulin resistance (IR) status, the risk of ASCVD and mortality among FH patients. Methods: Data from National Health and Nutrition Examination Survey (NHANES) 1999–2018 were utilized. 941 FH individuals with TyG index information were included and categorized into three groups: < 8.5, 8.5–9.0, and > 9.0. Spearman correlation analysis was used to test the association of TyG index and various established glucose metabolism-related indicators. Logistic and Cox regression analysis were used to assess the association of TyG index with ASCVD and mortality. The possible nonlinear relationships between TyG index and the all-cause or cardiovascular death were further evaluated on a continuous scale with restricted cubic spline (RCS) curves. Results: TyG index was positively associated with fasting glucose, HbA1c, fasting insulin and the homeostatic model assessment of insulin resistance (HOMA-IR) index (all p < 0.001). The risk of ASCVD increased by 74% with every 1 unit increase of TyG index (95%CI: 1.15–2.63, p = 0.01). During the median 114-month follow-up, 151 all-cause death and 57 cardiovascular death were recorded. Strong U/J-shaped relations were observed according to the RCS results (p = 0.0083 and 0.0046 for all-cause and cardiovascular death). A higher TyG index was independently associated with both all-cause death and cardiovascular death. Results remained similar among FH patients with IR (HOMA-IR ≥ 2.69). Moreover, addition of TyG index showed helpful discrimination of both survival from all-cause death and cardiovascular death (p < 0.05). Conclusion: TyG index was applicable to reflect glucose metabolism status in FH adults, and a high TyG index was an independent risk factor of both ASCVD and mortality.

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