Background The present study aimed to determine the protective effects of hypaconitine (HA) and glycyrrhetinic acid (GA) against chronic heart failure (CHF) in the rats and to explore the underlying molecular mechanisms. Methods The CHF rat model was established by transverse-aortic constriction (TAC) operation. Transthoracic echocardiography and hematoxylin eosin (HE) staining were used to evaluate the pathophysiological and histopathological changes of CHF model. The total cholesterol (TCHO) and triglyceride (TG) levels were determined by ELISA assay. The protein expression of fibroblast growth factor 2 (FGF2), vascular endothelial growth factor A (VEGFA) and endothelial nitric oxide synthase (eNOS) in the rat ventricular tissues was determined by immunohistochemistry. The serum metabolites were determined by LC-MS/MS assay. Results After applied the HA + GA, the cardiac tissue and structure were obviously improved, and the HA + GA treatment also significantly reduced the plasma levels of TCHO and TG in the CHF rats. The expression of FGF2 and VEGFA protein was up-regulated and the expression of eNOS protein was down-regulated in the ventricular tissues of CHF rats, which was significantly restored after HA + GA treatment. HA + GA treatment down-regulated serum isonicotinic acid, phosphatidylcholine, cardiolipin, estrogen glucuronide, and glycocholic acid, up-regulated serum sphingosine and deoxycholic acid in the CHF rats. Conclusions In conclusion, HA + GA showed protective effects on CHF in the rats, and the HA + GA may exert protective effects by reducing lipid levels, up-regulating the expression of FGF2 and VEGFA proteins, attenuating eNOS protein expression, and modulating metabolic pathways. However, the molecular mechanisms underlying HA + GA-mediated effects still require further examination.
Objectives We aimed to explore the potential role of N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), d ‐dimer, and the echocardiographic parameter left atrial diameter (LAD) in identifying and predicting the occurrence of ischemic stroke (IS) in patients with nonvalvular atrial fibrillation (NVAF). Methods We conducted a retrospective study of 445 patients with NVAF in the First Affiliated Hospital of Nanchang University. They were divided into the NVAF (309 cases) and NVAF with stroke (136 cases) groups according to whether acute ischemic stroke (AIS) occurred at admission. Multivariate logistic regression was used to analyze the odds ratio (OR) of NT‐proBNP, d ‐dimer, and LAD for IS. The predictive value of NT‐proBNP, d ‐dimer, and LAD in identifying the occurrence of IS in NVAF was determined by plotting the receiver operating characteristic (ROC) curves. Results NT‐proBNP, d ‐dimer, and LAD levels were significantly higher in the NVAF with stroke group than in the NVAF group ( p < .05). NT‐ProBNP, d ‐dimer, and LAD were independently associated with IS in NVAF patients (odds ratio [OR] = 1.12, 95% confidence interval [CI]: 1.08–1.16; OR = 1.87, 95% CI: 1.37–2.55; OR = 1.21, 95% CI: 1.13–1.28, p < .01). The optimal cutoff points for NT‐ProBNP, d ‐dimer, and LAD levels to distinguish the NVAF group from the NVAF with stroke group were 715.0 pg/ml, 0.515 ng/ml, and 38.5 mm, respectively, with the area under the curve (AUC) being [0.801 (95% CI: 0.76–0.84); 0.770 (95% CI: 0.72–0.85); 0.752 (95% CI: 0.71–0.80), p < .01]. The combined score of NT‐proBNP, d ‐dimer, and LAD improved the predictive efficacy of the single index, with an AUC of 0.846 (95% CI: 0.81–0.88, p < .01), sensitivity of 77.2%, and specificity of 76.4%. Conclusion NT‐proBNP, d ‐dimer, and the echocardiographic parameter LAD have outstanding value in predicting the risk of IS in patients with NVAF.
Background: Myocardial ischemia/reperfusion injury (MIRI) is a major cause of heart failure after myocardial infarction. It has been reported that miR-322 is involved in MIRI progression, while the molecular mechanism of miR-322 in regulating MIRI progression needs to be further probed.Methods: MIRI cell model was established by oxygen‐glucose deprivation/reoxygenation (OGD/R). Cell viability was assessed using MTS assay. Flow cytometry and TUNEL staining were employed to analyze cell apoptosis. In addition, the interactions between miR-322, Smad7/Smurf2, HIF-1α and β-catenin were verified by dual-luciferase reporter gene assay.Results: Our results displayed that miR-322 was significantly downregulated in OGD/R-treated H9c2 cells, and its overexpression resulted in increased cell viability and reduced the apoptosis. Smurf2 and Smad7 were identified as the direct targets of miR-322. Smad7 knockdown or Smurf2 knockdown increased OGD/R-treated H9c2 cell viability and suppressed the apoptosis. Meanwhile, miR-322 mimics abolished the mitigating effect of Smad7 or Smurf2 overexpression on MIRI. In addition, the Smad3/β-catenin pathway was identified as the downstream pathway of Smurf2/Smad7. Moreover, it was found that HIF-1α interacted with the miR-322 promoter, and β-catenin interacted with the HIF-1α promoter to form a loop.Conclusion: HIF-1α-induced up-regulated miR-322 activated the Smad3/β-catenin pathway by targeting Smurf2 and Smad7 to improve MIRI; meanwhile, β-catenin/ HIF-1α formed a positive feedback loop to continuously improve MIRI.
Myocardial ischemia/reperfusion injury (MIRI) is a prevalent condition associated with numerous critical clinical conditions. miR‐322 has been implicated in MIRI through poorly understood mechanisms. Our preliminary analysis indicated potential interaction of CREB‐binding protein (CBP), a transcriptional coactivator and acetyltransferase, with HIF‐1α/β‐catenin, which might regulate miR‐322 expression. We, therefore, hypothesized that CBP/HIF‐1α/β‐catenin/miR‐322 axis might play a role in MIRI. Rat cardiomyocytes subjected to oxygen‐glucose deprivation /reperfusion (OGD/R) and Langendorff perfused heart model were used to model MIRI in vitro and in vivo, respectively. We used various techniques such as CCK‐8 assay, transferase dUTP nick end labeling staining, western blotting, RT‐qPCR, chromatin immunoprecipitation (ChIP), dual‐luciferase assay, co‐immunoprecipitation (Co‐IP), hematoxylin and eosin staining, and TTC staining to assess cell viability, apoptosis, and the levels of CBP, HIF‐1α, β‐catenin, miR‐322, and acetylation. Our results indicate that OGD/R in cardiomyocytes decreased CBP/HIF‐1α/β‐catenin/miR‐322 expression, increased cell apoptosis and cytokines, and reduced cell viability. However, overexpression of CBP or miR‐322 suppressed OGD/R‐induced cell injury, while knockdown of HIF‐1α/β‐catenin further exacerbated the damage. HIF‐1α/β‐catenin bound to miR‐322 promoter to promote its expression, while CBP acetylated HIF‐1α/β‐catenin for stabilization. Overexpression of CBP attenuated MIRI in rats by acetylating HIF‐1α/β‐catenin to stabilize their expression, resulting in stronger binding of HIF‐1α/β‐catenin with the miR‐322 promoter and subsequent increased miR‐322 levels. Therefore, activating CBP/HIF‐1α/β‐catenin/miR‐322 signaling may be a potential approach to treat MIRI.
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