B-Type Natriuretic Peptide Inhibits the Expression and Function of SERCA2a in Heart Failure.

B-type natriuretic peptide (BNP) possesses protective cardiovascular properties; however, there has not been sufficient serious consideration of the side effects of BNP. As for sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a), it was once considered a new target for the treatment of heart failure (HF). Nevertheless, clinical trials of SERCA2a gene therapy in HF have finally become unsuccessful. Research has found that elevated BNP levels and decreased SERCA2a expression are two important HF characteristics, which are always negatively correlated. We hypothesize that BNP inhibits SERCA2a expression and, therefore, exerts negative effects on SERCA2a expression and function.The effects of BNP on endogenous SERCA2a expression and function were tested in mice with HF induced by transverse aortic constriction and neonatal rat cardiomyocytes (NRCM). Furthermore, to verify the effects of BNP on exogenous SERCA2a gene transduction efficacy, BNP was added to the myocardium and cardiomyocytes infected with an adenovirus overexpressing SERCA2a.In vivo, BNP levels were increased, SERCA2a expression was reduced in both the BNP intervention and HF groups, and BNP reduced the overexpressed exogenous SERCA2a protein in the myocardium. Our in vitro data showed that BNP dose-dependently inhibited the total and exogenous SERCA2a expression in NRCM by activating the cGMP-dependent protein kinase G. BNP also inhibited the effects of SERCA2a overexpression on Ca2+ transience in NRCM.The expression and function of endogenous and exogenous SERCA2a are inhibited by BNP. The opposite relationship between BNP and SERCA2a should be given serious attention in the treatment of HF via BNP or SERCA2a gene therapy.

Luteolin Pretreatment Ameliorates Myocardial Ischemia/Reperfusion Injury by lncRNA-JPX/miR-146b Axis.

Background: In the present study, we aimed to find out whether luteolin (Lut) pretreatment could ameliorate myocardial ischemia/reperfusion (I/R) injury by regulating the lncRNA just proximal to XIST (JPX)/microRNA-146b (miR-146b) axis. Methods: We established the models in vitro (HL-1 cells) and in vivo (C57BL/6J mice) to certify the protection mechanism of Lut pretreatment on myocardial I/R injury. Dual luciferase reporter gene assay was utilized for validating that JPX could bind to miR-146b. JPX and miR-146b expression levels were determined by RT-qPCR. Western blot was utilized to examine apoptosis-related protein expression levels, including cleaved caspase-9, caspase-9, cleaved caspase-3, caspase-3, Bcl-2, Bax, and BAG-1. Apoptosis was analyzed by Annexin V-APC/7-AAD dualstaining, Hoechst 33342 staining, as well as flow cytometry. Animal echocardiography was used to measure cardiac function (ejection fraction (EF) and fractional shortening (FS) indicators). Results: miR-146b was demonstrated to bind and recognize the JPX sequence site by dual luciferase reporter gene assay. The expression level of miR-146b was corroborated to be enhanced by H/R using RT-qPCR (P < 0.001 vs. Con). Moreover, JPX could reduce the expression of miR-146b, whereas inhibiting JPX could reverse the alteration (P < 0.001 vs. H/R, respectively). Western blot analysis demonstrated that Lut pretreatment increased BAG-1 expression level and Bcl-2/Bax ratio, but diminished the ratio of cleaved caspase 9/caspase 9 and cleaved caspase 3/caspase 3 (P < 0.001 vs. H/R, respectively). Moreover, the cell apoptosis change trend, measured by Annexin V-APC/7-AAD dualstaining, Hoechst 33342 staining, along with flow cytometry, was consistent with that of apoptosis-related proteins. Furthermore, pretreatment with Lut improved cardiac function (EF and FS) (P < 0.001 vs. I/R, respectively), as indicated in animal echocardiography. Conclusion: Our results demonstrated that in vitro and in vivo, Lut pretreatment inhibited apoptosis via the JPX/miR-146b axis, ultimately improving myocardial I/R injury.

Combination pharmacotherapies for cardiac reverse remodeling in heart failure patients with reduced ejection fraction: A systematic review and network meta-analysis of randomized clinical trials.

Pharmacotherapies, including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor II blockers (ARBs), ß-blockers (BBs), mineralocorticoid receptor antagonists (MRAs) and angiotensin receptor blocker-neprilysin inhibitor (ARNI), have played a pivotal role in reducing in-hospital and mortality in heart failure patients with reduced ejection fraction (HFrEF). However, effects of the five drug categories used alone or in combination for cardiac reverse remodeling (CRR) in these patients have not been systematically evaluated. A Bayesian network meta-analysis was conducted based on 55 randomized controlled trials published between 1989 and 2019 involving 12,727 patients from PubMed, EMBASE, Cochrane Library, and Clinicaltrials.gov. The study is registered with PROSPERO (CRD42020170457). Our primary outcomes were CRR indicators, including changes of left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV) and end-systolic volume (LVESV), indexed LVEDV (LVEDVI) and LVESV (LVESVI), and left ventricular end-diastolic dimension (LVEDD) and end-systolic dimension (LVESD); Secondary outcomes were functional capacity comprising New York Heart Association (NYHA) class and 6-min walking distance (6MWD); cardiac biomarkers involving B type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP). The effect sizes were presented as the mean difference with 95% credible intervals. According to the results, all dual-combination therapies except ACEI+ARB were significantly more associated with LVEF or NYHA improvement than placebo, ARB+BB and ARNI+BB were the top two effective dual-combinations in LVEF improvement (+7.59% [+4.27, +11.25] and +7.31% [+3.93, +10.97] respectively); ACEI+BB was shown to be superior to ACEI in reducing LVEDVI and LVESVI (-6.88 mL/m2 [-13.18, -1.89] and -10.64 mL/m2 [-18.73, -3.54] respectively); ARNI+BB showed superiority over ACEI+BB in decreasing the level of NT-proBNP (-240.11 pg/mL [-456.57, -6.73]). All tri-combinations were significantly more effective than placebo in LVEF improvement, and ARNI+BB+MRA ranked first (+21.13% [+14.34, +28.13]); ACEI+BB+MRA was significantly more associated with a decrease in LVEDD than ACEI (-6.57 mm [-13.10, -0.84]). A sensitivity analysis ignoring concomitant therapies for LVEF illustrated that all the five drug types except ARB were shown to be superior to placebo, and ARNI ranked first (+4.83% [+1.75, +7.99]). In conclusion, combination therapies exert more benefits on CRR for patients with HFrEF. Among them, ARNI+BB, ARB+BB, ARNI+BB+MRA and ARB+BB+MRA were the top two effective dual and triple combinations in LVEF improvement, respectively; The new "Golden Triangle" of ARNI+BB+MRA was shown to be superior to ACEI+BB+MRA or ARB+BB+MRA in LVEF improvement.