Isoproterenol-induced Heart Failure Research Articles

A novel histone deacetylase inhibitor Se-SAHA attenuates isoproterenol-induced heart failure via antioxidative stress and autophagy inhibition

Heart failure is associated with histone deacetylase (HDAC) regulation of gene expression, the inhibition of which is thought to be beneficial for heart failure therapy. Here, we explored the cardioprotective effects and underlying mechanism of a novel selenium-containing HDAC inhibitor, Se-SAHA, on isoproterenol (ISO)-induced heart failure. We found that pretreatment with Se-SAHA attenuated ISO-induced cardiac hypertrophy and fibrosis in neonatal rat ventricular myocytes (NRVMs). Se-SAHA significantly attenuated the generation of ISO-induced reactive oxygen species (ROS) and restored the expression levels of superoxide dismutase 2 (SOD2) and heme oxygenase-1 (HO-1) in vitro. Furthermore, Se-SAHA pretreatment prevented the accumulation of autophagosomes. Se-SAHA reversed the high expression of HDAC1 and HDAC6 induced by ISO incubation. However, after the addition of the HDAC agonist, the effect of Se-SAHA on blocking autophagy was inhibited. Using ISO-induced mouse models, cardiac ventricular contractile dysfunction, hypertrophy, and fibrosis was reduced treated by Se-SAHA. In addition, Se-SAHA inhibited HDAC1 and HDAC6 overexpression in ISO-treated mice. Se-SAHA treatment significantly increased the activity of SOD2 and improved the ability to eliminate free radicals. Se-SAHA hindered the excessive levels of the microtubule-associated protein 1 light chain 3 (LC3)-II and Beclin-1 in heart failure mice. Collectively, our results indicate that Se-SAHA exerts cardio-protection against ISO-induced heart failure via antioxidative stress and autophagy inhibition.

Cardio-protective and Antioxidant Potential of Pterocarpus marsupium heartwood extract on Isoproterenol induced heart failure in rats

Heart failure (HF) is a clinical syndrome characterised by a constellation of symptoms(dyspnea, orthopnea, lower limb swelling) and signs (elevated jugular venous pressure, pulmonary congestion) which have underlying cardiac abnormality resulting in reduced cardiac output and/or elevated intra-cardiac pressures. HF is a leading cause of mortality globally and despite major therapeutic advances, HF continues to cause substantial morbidity and mortality. Therefore, there is a need to develop new prophylactic and therapeutic strategies for HF. Isoproterenol (ISO) is a synthetic non-selective beta adrenoceptor agonist and is widely used to model toxic cardiomyopathy and heart failure. It induces myocyte damage mimicking myocardial infarction. In the present study, we used ISO to induce heart failure in Wistar rats and study the effect of Pterocarpus marsupium (PM) heartwood extract on it. PM is a well-recognised herbal drug known for its beneficial effect in diabetes with potential anti-inflammatory and anti-oxidative properties.Hypothesis: PM treatment will favourably modulate the cardiac hemodynamic, anti-oxidative stress and anti-inflammatory parameters compared to standard drug and control rats in isoproterenol induced heart failure rats.Methods & Results. Animals were randomly divided into 10 groups.1: Normal control rats fed normal pellet diet, 2: Normal control rats treated with Fluvastatin (10 mg/kg; oral gavage) for 15 days 3: Normal control rats treated with PM Extract (100 mg/kg; oral gavage) for 15 days. 4: Normal control rats subcutaneously injected with ISO {Heart Failure (HF) group} 5: HF rats treated with Fluvastatin (10 mg/kg; oral gavage) for 15 days. 6: HF rats treated with PM Extract (100 mg/kg; oral gavage) for 15days 7: HF rats treated with PM Extract (200mg/kg; oral gavage) for 15 days. 8: Rats pretreated with Fluvastatin (10 mg/kg; oral gavage) for 15 days and at the 15th day subcutaneously injected with ISO and continued Fluvastatin treatment for another 15 days 9: Rats pretreated with PM Extract (100 mg/kg; oral gavage) for 15 days and at the 15th day subcutaneously injected with ISO and continued PM Extract treatment for another 15 days 10: Rats pretreated with PM Extract (200 mg/kg; oral gavage) for 15 days and at the 15th day subcutaneously injected with ISO and continued PM treatment for another 15 days. The groups were compared pre and post treatment for cardiac hemodynamic parameters, anti- oxidative stress parameters (superoxide dismutase, nitric oxide, malondialdehyde nitric oxide), cardiac injury markers, anti-inflammatory parameters (Interleukin-6 and Tumor Necrosis Factor-α).The results of the present study indicate that prophylactic and therapeutic treatment PM heartwood extract improved the altered hemodynamic and biochemical parameters in isoproterenol-induced HF rats suggesting its cardio-protective action. None declared. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Cardiotoxicity of hydroalcoholic extract of Lepidium draba in isoproterenol-induced heart failure in rats

Cardiotoxicity of hydroalcoholic extract of Lepidium draba in isoproterenol-induced heart failure in rats

Shenfu injection improves isoproterenol-induced heart failure in rats by modulating co-metabolism and regulating the trimethylamine-N-oxide - inflammation axis.

Heart failure (HF) is a chronic condition that progressively worsens and continues to be a major financial burden and public health concern. The "gut-heart" axis provides an innovative perspective and therapeutic strategy for preventing and treating heart failure. Shenfu injection (SFI) is a Traditional Chinese Medicine-based treatment demonstrating potential as a therapeutic strategy for heart failure. However, the precise therapeutic mechanisms of SFI in heart failure are not completely characterized. In this study, HF models were established utilizing subcutaneous multipoint injection of isoproterenol (ISO) at a dosage of 5mgkg-1·d-1 for 7days. Serum levels of inflammatory biomarkers were quantified using protein microarrays. Rat feces were analyzed using untargeted metabolomics research and 16S rRNA sequencing. The link between gut microbiota and metabolites was examined using a MetOrigin and Spearman correlation analysis. Our results show that Shenfu injection effectively enhances cardiac function in rats with ISO-induced heart failure by potentially modulating pro-/anti-inflammatory imbalance and reducing serum and urine Trimethylamine-N-oxide (TMAO) levels. Moreover, SFI significantly increases the abundance of Bacteroidota at the phylum level, thereby improving disrupted gut microbiota composition. Additionally, SFI supplementation enriches specific genera known for their capacity to produce short-chain fatty acids. SFI was found to be associated with three key metabolic pathways, as revealed by fecal metabonomics analysis, including the pentose phosphate pathway, pyrimidine metabolism, and purine metabolism. Metabolite tracing analysis revealed that Taurine and hypotaurine metabolism was found to be specific to the microbial community. The biosynthesis of Pyrimidine metabolism, Purine metabolism, beta-alanine metabolism, Naphthalene degradation, Pantothenate, and CoA biosynthesis were identified as co-metabolic pathways between microbes and host. The Spearman correlation analysis was also significantly correlated to differentially expressed metabolites regulated by SFI and the gut microbiota. These results suggest that SFI improves ISO-induced heart failure by modulating co-metabolism and regulating the TMAO-inflammation axis.

Glyceraldehyde derivatives inspired by empagliflozin as potential anti-heart failure agents independent of glucose-lowering effects

Sodium-glucose cotransporter 2 inhibitors are a class of glucose-lowering drugs known for robust cardiovascular protective properties. However, the side effects induced by Sodium-glucose cotransporter 2 inhibition limit application in cardiovascular medicine. Our prior research showed that thoughtful structural modifications can dissociate the anti-heart failure activity from glucose-lowering effects. Moreover, we showed that the glyceraldehyde derivative, JX22, developed by scaffold hopping from empagliflozin, exhibits a superior cardiomyocyte protective effect, albeit with increased cytotoxicity compared to empagliflozin. In the current study systematic structural modifications of JX22 were performed to enhance anti-heart failure efficacy and safety, while reducing glucose-lowering activity. Twenty glyceraldehyde-based derivatives were synthesized and compound 12 emerged as an optimal candidate by exhibiting an improved cytoprotective effect compared to JX22. Compound 12 significantly inhibited the activity of NHE1 on the myocardial membrane, thereby maintaining intracellular ion homeostasis. In vivo efficacy results demonstrated that compound 12 at 10 mg/kg significantly ameliorated cardiac dysfunction, myocardial fibrosis, and exercise tolerance in isoproterenol-induced heart failure mice without a glucose-lowering effect. Furthermore, compound 12 exhibited favorable safety profiles in single-dose toxicity and hERG inhibition tests, along with promising pharmacokinetic properties in mice. The current study not only underscores the potential of compound 12 for further investigation but also highlights the effectiveness of the scaffold hopping strategy.

Cardioprotective effects of Moku-boi-to and its impact on AngII-induced cardiomyocyte hypertrophy.

Cardiomyocyte hypertrophy, induced by elevated levels of angiotensin II (AngII), plays a crucial role in cardiovascular diseases. Current therapeutic approaches aim to regress cardiac hypertrophy but have limited efficacy. Widely used Japanese Kampo medicines are highly safe and potential therapeutic agents. This study aims to explore the impact and mechanisms by which Moku-boi-to (MBT), a Japanese Kampo medicine, exerts its potential cardioprotective benefits against AngII-induced cardiomyocyte hypertrophy, bridging the knowledge gap and contributing to the development of novel therapeutic strategies. By evaluating the effects of six Japanese Kampo medicines with known cardiovascular efficiency on AngII-induced cardiomyocyte hypertrophy and cell death, we identified MBT as a promising candidate. MBT exhibited preventive effects against AngII-induced cardiomyocyte hypertrophy, cell death and demonstrated improvements in intracellular Ca2+ signaling regulation, ROS production, and mitochondrial function. Unexpectedly, experiments combining MBT with the AT1 receptor antagonist losartan suggested that MBT may target the AT1 receptor. In an isoproterenol-induced heart failure mouse model, MBT treatment demonstrated significant effects on cardiac function and hypertrophy. These findings highlight the cardioprotective potential of MBT through AT1 receptor-mediated mechanisms, offering valuable insights into its efficacy in alleviating AngII-induced dysfunction in cardiomyocytes. The study suggests that MBT holds promise as a safe and effective prophylactic agent for cardiac hypertrophy, providing a deeper understanding of its mechanisms for cardioprotection against AngII-induced dysfunction.

S14G-humanin confers cardioprotective effects against chronic adrenergic and pressure overload-induced heart failure in mice

S14G-humanin (HNG), an analog of the mitochondria-derived peptide humanin, has demonstrated protective effects against various cardiovascular diseases. However, the specific pharmacological effects of HNG in heart failure (HF) have not been previously reported. Therefore, in this study, we aimed to investigate the potential protective effect of HNG in HF using a mouse model. HF was induced in mice through intraperitoneal injection of isoproterenol or transverse aortic constriction, followed by separate administration of HNG to assess its therapeutic impact. Our results revealed that HNG treatment significantly delayed the onset of cardiac dysfunction and structural remodeling in the HF mouse model. Furthermore, HNG administration was associated with reduced infiltration of inflammatory cells, improved myocardial fibrosis, and attenuation of cardiomyocyte apoptosis in the treated cardiac tissues. Additionally, we identified the involvement of the transforming growth factor-beta signaling pathway in the beneficial effects of HNG in isoproterenol-induced HF mice. Collectively, these findings underscore the therapeutic potential of HNG in preventing the progression of HF, as demonstrated in two distinct HF mouse models.

Cardioprotective effects of Ganoderma lucidum on isoproterenol–induced heart failure

Cardioprotective effects of Ganoderma lucidum on isoproterenol–induced heart failure

Protocatechuic acid prevents isoproterenol-induced heart failure in mice by downregulating kynurenine-3-monooxygenase.

Protocatechuic acid (3,4-dihydroxybenzoic acid) prevents oxidative stress, inflammation and cardiac hypertrophy. This study aimed to investigate the therapeutic effects of protocatechuic acid in an isoproterenol-induced heart failure mouse model and to identify the underlying mechanisms. To establish the heart failure model, C57BL/6NTac mice were given high-dose isoproterenol (80 mg/kg body weight) for 14 days. Echocardiography revealed that protocatechuic acid reversed the isoproterenol-induced downregulation of fractional shortening and ejection fraction. Protocatechuic acid attenuated cardiac hypertrophy as evidenced by the decreased heart-weight-to-body-weight ratio and the expression of Nppb. RNA sequencing analysis identified kynurenine-3-monooxygenase (Kmo) as a potential target of protocatechuic acid. Protocatechuic acid treatment or transfection with short-interfering RNA against Kmo ameliorated transforming growth factor β1-induced upregulation of Kmo, Col1a1, Col1a2 and Fn1 in vivo or in neonatal rat cardiac fibroblasts. Kmo knockdown attenuated the isoproterenol-induced increase in cardiomyocyte size, as well as Nppb and Col1a1 expression in H9c2 cells or primary neonatal rat cardiomyocytes. Moreover, protocatechuic acid attenuated Kmo overexpression-induced increases in Nppb mRNA levels. Protocatechuic acid or Kmo knockdown decreased isoproterenol-induced ROS generation in vivo and in vitro. Thus, protocatechuic acid prevents heart failure by downregulating Kmo. Therefore, protocatechuic acid and Kmo constitute a potential novel therapeutic agent and target, respectively, against heart failure.

Triterpenoids with diverse skeletons from the roots of Rhus chinensis and their protective effects on isoproterenol-induced heart failure in zebrafish

In the ongoing quest to discover previously unreported lead compounds that provide protection against heart failure (HF), ten formerly undescribed (1–10) and nine known (11–19) triterpenoids were obtained from the roots of Rhus chinensis Mill. The isolated triterpenoids exhibited distinct skeletal types, including rare 17-epi-dammarane (1, 6, 7, 11, and 12), conventional dammarane (2–5, 8, and 9), oleanane (10 and 13–17) and lupane (18 and 19). Their structures were elucidated via a comprehensive analysis of the HRESIMS, NMR, and ECD data, as well as quantum chemical calculations of NMR parameters. Notably, compounds 1–5, 10–15, and 19 possessed an unusual 3,19 (or 25)-hemiketal structure bridging over ring A, while the remaining compounds were classified as 3-oxotriterpenoids. The skeletal diversity observed in these compounds was further elaborated from a biosynthetic perspective. Subsequently, the protective effects of fourteen compounds (1, 3, 4, 6–9, 11–14, and 16–18) against HF were evaluated using zebrafish models of isoproterenol-induced HF at a concentration of 1 μg/mL. Remarkably, all fourteen compounds significantly ameliorated pericardial edema, with five compounds (3, 6, 11, 14, and 16) also attenuating impaired cardiac output (CO), and eight compounds (1, 3, 4, 7–9, 14, and 16) inhibiting cardiomyocyte apoptosis. Notably, certain compounds even restored the impaired pericardium and CO to near-normal levels. These findings highlight the therapeutic potential of triterpenoids derived from R. chinensis as promising agents for the treatment of HF.

Genetic architecture of heart mitochondrial proteome influencing cardiac hypertrophy.

Mitochondria play an important role in both normal heart function and disease etiology. We report analysis of common genetic variations contributing to mitochondrial and heart functions using an integrative proteomics approach in a panel of inbred mouse strains called the Hybrid Mouse Diversity Panel (HMDP). We performed a whole heart proteome study in the HMDP (72 strains, n=2-3 mice) and retrieved 848 mitochondrial proteins (quantified in ≥50 strains). High-resolution association mapping on their relative abundance levels revealed three trans-acting genetic loci on chromosomes (chr) 7, 13 and 17 that regulate distinct classes of mitochondrial proteins as well as cardiac hypertrophy. DAVID enrichment analyses of genes regulated by each of the loci revealed that the chr13 locus was highly enriched for complex-I proteins (24 proteins, P=2.2E-61), the chr17 locus for mitochondrial ribonucleoprotein complex (17 proteins, P=3.1E-25) and the chr7 locus for ubiquinone biosynthesis (3 proteins, P=6.9E-05). Follow-up high resolution regional mapping identified NDUFS4, LRPPRC and COQ7 as the candidate genes for chr13, chr17 and chr7 loci, respectively, and both experimental and statistical analyses supported their causal roles. Furthermore, a large cohort of Diversity Outbred mice was used to corroborate Lrpprc gene as a driver of mitochondrial DNA (mtDNA)-encoded gene regulation, and to show that the chr17 locus is specific to heart. Variations in all three loci were associated with heart mass in at least one of two independent heart stress models, namely, isoproterenol-induced heart failure and diet-induced obesity. These findings suggest that common variations in certain mitochondrial proteins can act in trans to influence tissue-specific mitochondrial functions and contribute to heart hypertrophy, elucidating mechanisms that may underlie genetic susceptibility to heart failure in human populations.

Intravenous Semaphorin 3A Administration Maintains Cardiac Contractility and Improves Electrical Remodeling in a Mouse Model of Isoproterenol-Induced Heart Failure.

The effects of recombinant semaphorin 3A (Sema3A) on myocardial contractility and electrical remodeling in mice with isoproterenol (ISP) -induced heart failure were investigated.C57BL/6J mice intraperitoneally received ISP (480 mg/kg/day, ISP group; n = 24) or saline (control group; n = 31) for 14 days. Twenty-one ISP-treated mice received 0.5 mg/kg Sema3A intravenously on days 7 and 11 (ISP+Sema3A group). The sympathetic nervous system was activated upon ISP treatment, but was reduced upon Sema3A administration. Greater myocardial tissue fibrosis was observed in the ISP group than in the control group. However, fibrosis was not significantly different between the ISP+Sema3A and control groups. Fractional shortening of the left ventricle was lower in the ISP group than in the control group and was restored in the ISP+Sema3A group (control, 53 ± 8%; ISP, 37 ± 7%; ISP+Sema3A, 48 ± 3%; P < 0.05). Monophasic action potential duration at 20% repolarization (MAPD20) was prolonged in the ISP group (compared to control group), but this was reversed upon Sema3A administration (control, 29 ± 3 ms; ISP, 35 ± 6 ms; ISP+Sema3A, 29 ± 3 ms; P < 0.05). qPCR revealed Kv4.3, KChIP2, and SERCA2 downregulation in the ISP group and upregulation in the ISP+Sema3A group; however, Western blotting revealed similar changes only for Kv4.3 (P < 0.05).Intravenous Sema3A may maintain myocardial contractility by suppressing the sympathetic innervation of the myocardium and reducing myocardial tissue damage, in addition to restoring MAPD via Kv4.3 upregulation.

Inhibition of transglutaminase 2 (TG2) ameliorates ventricular fibrosis in isoproterenol-induced heart failure in rats

AimsTransglutaminase (TG) inhibitors represent promising therapeutic interventions in cardiac fibrosis and related dysfunctions. However, it remains unknown how TG inhibition, TG2 in particular, affects the signaling systems that drive pathological fibrosis. This study aimed to examine the effect TG inhibition by cystamine on the progression of isoproterenol (ISO)-induced cardiac fibrosis and dysfunction in rats. Materials and methodsCardiac fibrosis was established by intraperitoneal injection of ISO to rats (ISO group), followed by 6 weeks of cystamine injection (ISO + Cys group). The control groups were administered normal saline alone or with cystamine. Hemodynamics, lipid profile, liver enzymes, urea, and creatinine were assessed in conjunction with heart failure markers (serum NT-proANP and cTnI). Left ventricular (LV) and atrial (LA) fibrosis, total collagen content, and mRNA expression of profibrotic markers including TG2 were quantified by Masson's trichrome staining, LC-MS/MS and quantitative PCR, respectively. Key findingsCystamine administration to ISO rats significantly decreased diastolic and mean arterial pressures, total cholesterol, triglycerides, LDL, liver enzymes, urea, and creatinine levels, while increasing HDL. NT-proANP and cTnI serum levels remained unchanged. In LV tissues, significant reductions in ISO-induced fibrosis and elevated total collagen content were achieved after cystamine treatment, together with a reduction in TG2 concentration. Reduced mRNA expression of several profibrotic genes (COL1A1, FN1, MMP-2, CTGF, periostin, CX43) was also evidenced in LV tissues of ISO rats upon cystamine administration, whereas TGF-β1 expression was depressed in LA tissues. Cystamine decreased TG2 mRNA expression in the LV of control rats, while LV expression of TG2 was relatively low in ISO rats irrespective of cystamine treatment. SignificanceTG2 inhibition by cystamine in vivo exerted cardioprotective effects against ISO-induced cardiac fibrosis in rats decreasing the LV abundance of several profibrotic markers and the content of TG2 and collagen, suggesting that TG2 pharmacological inhibition could be beneficial to alleviate cardiac fibrosis.

Celastrol Improves Isoproterenol-Induced Heart Failure by Reducing Inflammation, Apoptosis and Oxidative Stress

Celastrol Improves Isoproterenol-Induced Heart Failure by Reducing Inflammation, Apoptosis and Oxidative Stress

Oxymatrine attenuated isoproterenol-induced heart failure via the TLR4/NF-κB and MAPK pathways in vivo and in vitro

Oxymatrine (OMT) is a quinoline alkaloid isolated from the root of the Sophora flavescens that has a variety of biological activities. However, the effect and potential mechanism of OMT on isoproterenol (ISO)-induced heart failure (HF) are not clear. In this study, we found that OMT improved the survival of HL-1 cells induced by ISO. We also demonstrated that OMT significantly inhibited the levels of the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). OMT decreased the levels of the TLR4 and reduced the phosphorylation levels of nuclear factor-κB (NF-κB) inhibitor (IκB), p65, c-Jun N-terminal kinases (JNK) and p38. The inhibitory effect of the TLR4 inhibitor TAK242 on HL-1 cells was evaluated. The results showed that the effect of OMT on the phosphorylation levels of IκBα and p65 was enhanced in HL-1 cells treated with TAK242. Using animal models, OMT significantly reduced ISO-induced cardiac injury, myocardial necrosis, interstitial edema, and fibrosis. In addition, OMT attenuated TNF-α and IL-6 and inhibited the expression of TLR4/NF-κB and MAPK pathway-related proteins. This finding suggests that OMT may alleviate HF by interfering with the TLR4/NF-κB and MAPK pathways.

Sodium houttuyfonate against cardiac fibrosis attenuates isoproterenol-induced heart failure by binding to MMP2 and p38

BackgroundHeart failure (HF), caused by stress cardiomyopathy, is a major cause of mortality. Cardiac fibrosis is an essential structural remodeling associated with HF; therefore, preventing cardiac fibrosis is crucial to decelerating the progression of HF. Sodium houttuyfonate (SH), an extract of Houttuynia cordata, has a potent therapeutic effect on hypoxic cardiomyocytes in a myocardial infarction model. PurposeTo investigate the preventative and therapeutic effects of SH during isoproterenol (ISO)-induced HF and explore the pharmacological mechanism of SH in alleviating HF. MethodsWe analyzed the overlapping target genes between SH and cardiac fibrosis or HF using a network pharmacology analytical method. We verified the suppressive effect of SH on ISO-induced proliferation and activation of cardiac fibroblasts by immunohistochemical staining and histological analysis in an isoproterenol-induced HF mouse model. Additionally, we investigated the effect of SH by evaluating fibrosis and cardiac remodeling markers. To further decipher the pharmacological mechanism of SH against cardiac fibrosis and HF, we performed a molecular docking analysis between SH and hub common target genes. ResultsThere were 20 overlapping target genes between SH and cardiac fibrosis and 32 overlapping target genes between SH and HF. The 16 common target genes of SH against cardiac fibrosis and HF included MMP2 (matrix metalloproteinase 2), and p38. SH significantly inhibited the ISO- or TGF-β-induced expression of Col1α (collagen 1), α-SMA (smooth muscle actin), MMP2, TIMP2 (tissue inhibitor of metalloproteinase 2), TGF-β (transforming growth factor), and Smad2 phosphorylation. Moreover, both ISO- and TGF-β-induced p38 phosphorylation was inhibited. Molecular docking analysis showed that SH forms a stable complex with MMP2 and p38. ConclusionsIn addition to protecting cardiomyocytes, SH directly inhibits cardiac fibroblast activation and proliferation by binding to MMP2 and p38, subsequently delaying cardiac fibrosis and HF progression. Our prevention- and intervention-based approaches in this study showed that SH inhibited the development of stress cardiomyopathy-mediated cardiac fibrosis and HF when SH was administered before or after the initiation of cardiac stress.

Shexiang Baoxin Pills Could Alleviate Isoproterenol-Induced Heart Failure Probably through its Inhibition of CaV1.2 Calcium Channel Currents.

Heart failure (HF) affects millions of patients in the world. Shexiang Baoxin Pills (SXB) are extensively applied to treat coronary artery diseases and HF in Chinese hospitals. However, there are still no explanations for why SXB protects against HF. To assess the protective role, we created the HF model in rats by isoproterenol (ISO) subcutaneous injection, 85 milligrams per kilogram body weight for seven days. Four groups were implemented: CON (control), ISO (HF disease group), CAP (captopril, positive drug treatment), and SXB groups. Echocardiography was used to evaluate rats' HF in vivo. The human CaV1.2 (hCaV1.2) channel currents were detected in tsA-201 cells by patch clamp technique. Five different concentrations of SXB (5, 10, 30, 50, and 100 mg/L) were chosen in this study. The results showed that SXB increased cardiac systolic function and inhibited rats' cardiac hypertrophy and myocardial fibrosis induced by ISO. Subsequently, it was found that SXB was inhibited by the peak amplitudes of hCaV1.2 channel current (P < 0.01). The SXB half inhibitory dosage was 9.09 mg/L. The steady-state activation curve was 22.8 mV depolarization shifted; while the inactivation curve and the recovery from inactivation were not affected significantly. In conclusion, these results indicated that SXB inhibited ISO-induced HF in rats and inhibited the hCaV1.2 channel current. The present study paved the way for SXB to protect itself from HF.

Salviae miltiorrhizae Liguspyragine Hydrochloride and Glucose Injection Protects against Myocardial Ischemia-Reperfusion Injury and Heart Failure.

Purpose Myocardial ischemia-reperfusion (MIR) injury is a common stimulus for cardiac diseases like cardiac arrhythmias and heart failure and may cause high mortality rates. Salviae miltiorrhizae liguspyragine hydrochloride and glucose injection (SGI) has been widely used to treat myocardial and cerebral infarctions in China even though its pharmacological mechanisms are not completely clear. Methods The protective effect and mechanism of SGI on MIR injury and heart failure were investigated through the H9c2 cell model induced by hypoxia/reoxygenation (H/R) and rapamycin, zebrafish model induced by H/R and isoprenaline, and rat MIR model. Results SGI significantly reduced the infarct size and alleviated the impairment of cardiac functions in the MIR rat model and H/R zebrafish model and promoted cell viability of cardiomyocyte-like H9c2 cells under H/R condition. Consistently, SGI significantly downregulated the serum level of biomarkers for cardiac damage and attenuated the oxidative damage in the MIR and H/R models. We also found that SGI could downregulate the increased autophagy level in those MIR and H/R models since autophagy can contribute to the injurious effects of ischemia-reperfusion in the heart, suggesting that SGI may alleviate MIR injury via regulating the autophagy pathway. In addition, we demonstrated that SGI also played a protective role in the isoproterenol-induced zebrafish heart failure model, and SGI significantly downregulated the increased autophagy and SP1/GATA4 pathways. Conclusion SGI may exert anti-MIR and heart failure by inhibiting activated autophagy and the SP1/GATA4 pathway.

Effect of Secreted Frizzled-Related Protein 5 in Mice with Heart Failure.

Although some progress has been made in its treatment, heart failure is still one of the most important health problems that endanger public health. This study aims to explore the myocardial protective effect of secreted frizzled-related protein 5 (SFRP5) on mice with heart failure. The mouse model of heart failure was established by using the isoproterenol (ISO) hydrochloride gradient modeling method. The treatment group was injected with 0.02 mg/kg/24 h SFRP5 recombinant protein intraperitoneally 30 minutes after the injection of isoproterenol, and the ISO + phosphate-buffered saline (PBS) group was injected with the same amount of PBS. After intraperitoneal injection of SFRP5 recombinant protein in mice with heart failure, the inflammatory response was reduced, and the left ventricular systolic and diastolic function of heart failure mice and the pathological structure of the myocardial tissue were improved. Compared with the ISO group, the expression level of SFRP5 protein in the ISO + SFRP5 group was increased significantly, the expression levels of Wnt5a and JNK protein were decreased markedly, and the enzyme activities of SOD and GSH-Px in the serum were observably increased, but they were lower than those parameters in the normal group. The SFRP5 recombinant protein has a protective effect on isoproterenol-induced heart failure in mice. The mechanism of action may be related to inhibiting the Wnt5A/JNK signaling pathway and reducing oxidative stress and inflammation. SFRP5 may be one of the therapeutic targets of heart failure.

Oral Administration of Euglena Gracilis Z Alleviates Constipation and Cardiac Dysfunction in a Mouse Model of Isoproterenol-Induced Heart Failure.

Background: Patients with heart failure (HF) often experience gastrointestinal problems such as constipation, diarrhea, and disturbances to drug absorption. In HF, hypoperfusion and congestion cause structural and functional changes in the gut, which, in turn, lead to impaired cardiac function. Euglena gracilis Z (hereafter “Euglena”), called Midorimushi in Japanese, is a microalga that is used as a food or nutritional supplement. It is unclear whether Euglena is beneficial for bowel habitus and cardiac function in subjects with HF. Methods and Results: We injected C57BL/6 male mice subcutaneously with isoproterenol (ISO) (20 mg/kg/day) for 7 days to examine bowel movement in HF. Euglena was orally administered to mice on an ad libitum-feeding to a normal chow containing 2% dietary mixture. ISO induced a decrease in bowel movement and an increase in fecal retention in the cecum, as well as a decrease in left ventricular (LV) contraction. Euglena accelerated intestinal transit, relieved fecal retention, and prevented the alterations in gut pathology in ISO-treated mice. Euglena also suppressed ISO-induced decreases in LV contraction, although it had no significant effect on LV hypertrophy. Conclusions: The results suggested that oral administration of Euglena alleviated constipation and cardiac dysfunction in a mouse model of ISO-induced HF, and highlight the potential clinical benefit of Euglena in patients with HF in preventing constipation and contractile deterioration.