Cardioprotective Agent Research Articles

Abstract P1041: Redox Regulator MnTnBuOE-PyP5+ Protects Cardiomyocyte Against Oxidative Stress Mediated Myocardial Ischemia/reperfusion Injury

Background: Much evidence suggests that oxidative stress plays a major role in the pathogenesis of myocardial ischemia/reperfusion (I/R) injury and is a potential target for therapeutic interventions. We tested the hypothesis that the novel redox regulator, MnTnBUOE-2-PyP 5+ (BMX-001), mediates cardioprotection through reduction of oxidative stress in myocardial tissue following I/R injury. Methods and Results: BMX-001 (2mg/Kg, IP) or vehicle was administered in mice 4 hours before myocardial ischemia. Mice were then subjected to I/R injury by ligating the left anterior descending artery for 1 hour followed by 24 hours of reperfusion. Following 24 hours of reperfusion, infarct size, cardiomyocyte apoptosis, and SOD2 level were determined, and echocardiography was performed. Our study revealed that the redox regulator provided protection against I/R-induced injury in mice as evident by a significant reduction in infarct size, plasma LDH level, and oxidative stress. In addition, BMX-001 administration in mice markedly increased FoxO3a and SOD2 levels. BMX-001 treatment attenuated I/R induced cardiomyocyte apoptosis in-vivo and in-vitro as evident by a reduction in the number of TUNEL positive cells and improved cell viability. Echocardiography at 24 hours of reperfusion revealed improved ejection fraction and fractional shortening in mice treated with BMX-001. Furthermore, in-vitro treatment of BMX-001 (10μM) 24 hours before hypoxia/reoxygenation in H9c2 cells improved oxidative stress as evident by a reduction in cardiolipin peroxidation, mitochondrial superoxide level, and 4-HNE adducted proteins. Conclusion: Pre-treatment with redox regulator BMX-001 showed a beneficial effect in attenuating cardiomyocyte death, mitochondrial superoxide, and cardiolipin peroxidation following I/R injury in H9c2 cells. Pre-treatment with SOD2 mimetic improved heart function, decreased infarct size, and cardiomyocyte apoptosis in mice following I/R injury. Therefore, BMX-001 can be a novel cardioprotective agent against oxidative stress-induced myocardial I/R injury.

Abstract P3115: The Protective Effect Of Canagliflozin Against Carfilzomib-induced Endothelial Toxicity

Introduction: The anti-cancer agent carfilzomib (CFZ) is associated with serious cardiovascular side effects. There is anecdotal clinical evidence that endothelial dysfunction contributes to CFZ-induced cardiovascular complications; however, the toxic effects of CFZ have not been reported in endothelial cells (ECs). The anti-diabetic Sodium glucose cotransporter 2 (SGLT 2 ) inhibitors have newly emerged as cardio-protective agents in heart failure, myocardial infarction, stroke, and diabetic cardiomyopathy. The objectives of the current work are to characterize the toxic effects of CFZ in two human-derived endothelial cell lines, human umbilical vein endothelial cells (HUVECs) and EA.hy926, determine the molecular signaling changes associated with these toxic effects, and investigate the protective effects of SGLT 2 inhibitors (Empagliflozin, Dapagliflozin, Canagliflozin) on CFZ-induced endothelial toxicity. Methods: Both ECs were treated with clinically relevant concentrations of CFZ (0.05, 0.1, 0.2, 0.5, and 1 μM) for 24 hours. EA.hy926 cells were treated with 0.5 μM CFZ with or without SGLT 2 inhibitor (0.1, 1, 10, 50, 100 μM). Cell viability was determined by the MTT assay and protein expressions of apoptotic markers, mitogen-activated protein kinases (MAPKs), and the p70S6K pathway were determined by western blotting. Results: CFZ reduces cell viability and induces apoptotic cell death in the two cell lines in a concentration-dependent manner. CFZ-induced apoptosis is also associated with activation of the p38 and JNK MAPK pathways and a remarkable inhibition of the p70S6K pathway. In EA.hy926, Canagliflozin prevents reduction in cell viability caused by CFZ, while empagliflozin and dapagliflozin have not shown any protective effects in vitro. Mechanistically, canagliflozin abrogates CFZ-induced endothelial cell apoptosis, and prevents CFZ-induced JNK activation. Conclusion: This is the first study to report the endothelial toxicity of CFZ. CFZ induces endothelial cell apoptosis which may contribute to CFZ-induced cardiovascular complications and canagliflozin protects against CFZ endothelial toxicity. Future research is warranted to identify the protective effects of SGLT 2 inhibitors against CFZ in vivo.

Angiotensin receptor-neprilysin inhibitor (thiorphan/irbesartan) improved cardiac function in a rat model of myocardial ischemic reperfusion injury.

Mitochondria-mediated apoptosis plays a critical role in myocardial ischemia reperfusion (IR) injury and causes a negative impact on cardiac efficiency and function. The combined angiotensin receptor-neprilysin inhibitor (ARNI) is a promising cardioprotective pharmacological agent that could rescue the heart from IR injury. This study investigated the cardioprotective effect of thiorphan (TH) in combination with three different doses of irbesartan (IRB) on myocardial IR injury and detected the most effective dose combination. Male Wistar rats were used and divided into five groups (10 rats/group): (I) Sham, (II) ischemia-reperfusion I/R, (III) TH/IRB + IR (0.1/5mg/kg), (IV) TH/IRB + IR (0.1/10mg/kg), and (V) TH/IRB + IR (0.1/15 mg/kg) groups. Thiorphan and irbesartan were injected intraperitoneally 15 min before IR induction. Mean arterial blood pressure, left ventricular end diastolic pressure (LVEDP), left ventricular maximum rate of pressure (LVdp/dtmax ), and cardiac levels of creatine kinase-MB, malondialdehyde, superoxide dismutase, and endothelin-1 were measured. Cardiac mitochondria complexes activities, histopathological examination of myocardial tissues, immunohistochemistry studies for myocardial apoptosis (Bax and Bcl-2), and electron microscopy examination of left ventricle were performed. TH/IRB combination preserved cardiac functions and mitochondria complex activities and mitigated cardiac damage, oxidative stress, and apoptosis following IR. Also, there was an evident improvement in histopathological changes and electron microscopy examination of left ventricle compared with I/R group. TH/IRB in a dose of 0.1/10mg/kg showed significant improvement compared with the other treated groups. Thiorphan/irbesartan improved cardiac functions following IR injury. This could be explained by the reported improvement of mitochondria complex activities and reduction of oxidative stress, endothelin-1, and apoptosis.

County-level variation in cardioprotective antihyperglycemic prescribing among medicare beneficiaries

BackgroundCardioprotective antihyperglycemic agents, SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP1RA), improve outcomes of patients with type 2 diabetes, but adoption has been limited. Differences across individuals have been noted but area-level variation is unknown. ObjectivesGiven healthcare access and sociodemographic differences, we evaluated whether SGLT2i and GLP-1RA utilization varies across US counties. MethodsWe linked 2019 Medicare Part D national prescription data with county-level demographic measures from the Agency for Health Quality and Research. We compared the number of beneficiaries receiving prescriptions for any cardioprotective antihyperglycemic to the number receiving metformin prescriptions across US counties. In multivariable linear regression with SGLT2i-to-metformin and GLP1RA-to-metformin prescriptions as outcomes, we evaluated county factors associated with use of cardioprotective agents while adjusting for sociodemographic measures, region, and cardiometabolic risk factor prevalence. ResultsIn 3066 US counties, there were a median 2,416 (IQR, 1681–3190) metformin-receiving beneficiaries per 100,000 population. A median 6.2% of beneficiaries receiving metformin received SGLT2i therapy, varying across counties (IQR, 3.4%–9.2%). A median 9.4% (IQR, 5.0%–13.0%) of beneficiaries receiving metformin received GLP-1RA. In adjusted analyses, higher percentage of Black population was associated with lower use at the county level of people on SGLT2i or GLP-1RA relative to metformin (a SD higher proportion of Black individuals with 0.4% [95% CI, -0.6% to -0.1%] and 0.5% [-0.8% to -0.2%] lower SGLT2i and GLP-1RA prescribing relative to metformin, respectively; P < 0.01). A higher median age of county residents, rural location, and lower prevalence of diabetes were associated with lower SGLT2i prescribing. Similarly, more advanced age of county residents, rural location, proportion of Hispanic individuals, and household income and lower education levels were associated with lower GLP-1RA prescribing. Prescribing was higher in the Northeast and lower in the West as compared with the Midwest for both classes. ConclusionThere was large variation by county in cardioprotective antihyperglycemic prescribing, with a pattern of lower use in Black-predominant and rural counties, highlighting the critical need to investigate equity in uptake of novel therapeutic agents.

Tetramisole is a new IK1 channel agonist and exerts IK1 -dependent cardioprotective effects in rats.

Cardiac ischemia, hypoxia, arrhythmias, and heart failure share the common electrophysiological changes featured by the elevation of intracellular Ca2+ (Ca2+ overload) and inhibition of the inward rectifier potassium (IK1) channel. IK1 channel agonists have been considered a new type of anti‐arrhythmia and cardioprotective agents. We predicted using a drug repurposing strategy that tetramisole (Tet), a known anthelminthic agent, was a new IK1 channel agonist. The present study aimed to experimentally identify the above prediction and further demonstrate that Tet has cardioprotective effects. Results of the whole‐cell patch clamp technique showed that Tet at 1–100 μmol/L enhanced IK1 current, hyperpolarized resting potential (RP), and shortened action potential duration (APD) in isolated rat cardiomyocytes, while without effects on other ion channels or transporters. In adult Sprague–Dawley (SD) rats in vivo, Tet showed anti‐arrhythmia and anticardiac remodeling effects, respectively, in the coronary ligation‐induced myocardial infarction model and isoproterenol (Iso, i.p., 3 mg/kg/day, 10 days) infusion‐induced cardiac remodeling model. Tet also showed anticardiomyocyte remodeling effect in Iso (1 μmol/L) infused adult rat ventricular myocytes or cultured H9c2 (2‐1) cardiomyocytes. Tet at 0.54 mg/kg in vivo or 30 μmol/L in vitro showed promising protections on acute ischemic arrhythmias, myocardial hypertrophy, and fibrosis. Molecular docking was performed and identified the selective binding of Tet with Kir2.1. The cardioprotection of Tet was associated with the facilitation of IK1 channel forward trafficking, deactivation of PKA signaling, and inhibition of intracellular calcium overload. Enhancing IK1 may play dual roles in anti‐arrhythmia and antiventricular remodeling mediated by restoration of Ca2+ homeostasis.

Change of renal function after short-term use of cardioprotective agents in patients with type 2 diabetes is not accurately assessed by the change of estimated glomerular filtration rate: an observational study

BackgroundAfter initiating cardioprotective agents, a fall of estimated glomerular filtration rate (eGFR) has been reported in several studies. Our goal was to evaluate the accuracy of change of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR in patients with type 2 diabetes (T2D) after short-term pharmacological intervention with angiotensin-converting enzyme inhibitor, angiotensin-receptor blocker, gliptin or sodium-glucose cotransporter-2 inhibitor.MethodsWe analyzed 190 patients with T2D in the early stage of the disease, having no overt renal impairment by CKD-EPI equation. In each patient, we measured GFR (mGFR) by applying the constant infusion input clearance technique with sinistrin (Inutest; Fresenius, Linz, Austria) at baseline and after short-term (4–12 weeks) pharmacological intervention with cardioprotective agents (ramipril, telmisartan, linagliptin, metformin, empagliflozin) that potentially lead to an alteration of renal function. Simultaneously, a standardized analysis of serum creatinine was performed and eGFR was estimated by the CKD-EPI equation.ResultsAverage mGFR was 111 ± 20 ml/min/1.73m2, whereas eGFR was lower with 93 ± 13 ml/min/1.73m2. The ratio eGFR/mGFR in relation to mGFR was almost curvilinear, showing an underestimation of renal function by eGFR in the upper normal range. At baseline only 80 patients (42%) lay within ± 10% of mGFR and the concordance correlation coefficient (CCC) was extremely low (− 0.07). After short-term pharmacological intervention changes in eGFR and mGFR correlated with each other (r = 0.286, p < 0.001). For example, for a given mGFR of 111 ml/min/1.73m2, a change of mGFR by ± 10% corresponded to ± 11 ml/min/1.73m2, but the confidence interval of eGFR was 25 ml/min/1.73m2. The CCC was low (0.22).ConclusionThe agreement between eGFR by CKD-EPI and mGFR is modest and the change of renal function after short-term pharmacological intervention is not accurately and precisely reflected by the change of eGFR in patients with T2D in the early stage of their disease.

Bergenin from Bergenia Species Produces a Protective Response against Myocardial Infarction in Rats

Bergenin is a phenolic glycoside that has been reported to occur naturally in several plant species, reported as a cardioprotective. However, bergenin, one of the important phytochemicals in these plants, is still not reported as a cardioprotective. The present study was designed to investigate the cardioprotective effects of bergenin on isoproterenol-induced myocardial infarction in rats. Bergenin and atenolol were administered through intraperitoneal (i.p.) injection to Sprague Dawley (SD) rats in separate experiments for five (5) days. At the end of this period, rats were administered isoproterenol (80 mg/kg s.c.) to induce myocardial injury. After induction, rats were anaesthetized to record lead II ECG, then sacrificed, blood was collected to analyze cardiac marker enzymes, and a histopathological study of the heart tissues was also performed. Pretreatment with bergenin showed a significant decrease in ST-segment elevation, deep Q-wave, infarct size, and also normalized cardiac marker enzymes (cTnI, CPK, CK-MB, LDH, ALT, and AST), particularly at 3 mg/kg, as compared to isoproterenol treated group. Our findings revealed, for the first time, the use of glycoside bergenin as a potential cardioprotective agent against the isoproterenol-induced MI in rats.

Juglone from Walnut Produces Cardioprotective Effects against Isoproterenol-Induced Myocardial Injury in SD Rats.

Therapeutic and/or preventive interventions using phytochemical constituents for ischemic heart disease have gained considerable attention worldwide, mainly due to their antioxidant activity. This study investigated the cardioprotective effect and possible mechanism of juglone, a major constituent of the walnut tree, using an isoproterenol (ISO)-induced myocardial infarction (MI) model in rats. Rats were pretreated for five (5) days with juglone (1, 3 mg/kg, i.p) and atenolol (1 mg/kg, i.p) in separate experiments before inducing myocardial injury by administration of ISO (80 mg/kg, s.c) at an interval of 24 h for 2 consecutive days (4th and 5th day). The cardioprotective effect of juglone was confirmed through a lead II electrocardiograph (ECG), cardiac biomarkers (cTnI, CPK, CK-MB, LDH, ALT and AST) and histopathological study. The results of our present study suggest that prior administration of juglone (1 and 3 mg/kg) proved to be effective as a cardioprotective therapeutic agent in reducing the extent of myocardial damage (induced by ISO) by fortifying the myocardial cell membrane, preventing elevated T-waves, deep Q-waves in the ECG, heart to body weight ratio, infarction and also by normalizing cardiac marker enzymes (cTnI, CPK, CK-MB, LDH, ALT and AST) and histopathological changes, such as inflammation, edema and necrosis. In conclusion, this study has identified phytochemical constituents, in particular juglone, as a potential cardioprotective agent.

Structural analysis of dexrazoxane: Exploring tautomeric conformations

Structural analysis of dexrazoxane, as a cardioprotective agent, was done in this work by exploring formations of tautomeric conformations and investigating the corresponding effects. Density functional theory (DFT) calculations were performed to optimize the structures to evaluate their molecular and atomic descriptors. In addition to the original structure of dexrazoxane, eight tautomers were obtained with lower stability than the original compound. Movements of two hydrogen atoms in between nitrogen and oxygen atoms of heterocyclic ring put such significant effects. Moreover, electronic molecular orbital features showed effects of such tautomerism processes on distribution patterns and surfaces, in which evaluating the quadrupole coupling constants helped to show the role of atomic sites for resulting the features. As a consequence, the results indicated that the tautomeric formations could significantly change the features of dexrazoxane reminding the importance of carful medication of this drug for patients.

Сardioprotective agents with biaromatic structure. Part 2. HCN channel blockers

Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels, primarily their HCN4 subtype, are one of the promising targets for the development of cardioprotective agents. HCN channel blockers have a selective bradycardic effect, preserving myocardial contractility and diastolic function and not affecting the electrophysiological parameters of the heart. This review continues a series of reviews on the analysis of compounds with cardioprotective properties in a number of biaromatic structures, which include a wide range of HCN channel blockers.

Novel purine analogues regulate IL-1β release via inhibition of JAK activity in human aortic smooth muscle cells

Purine analogues bearing a nitrate ester motif were previously discovered as cardioprotective and anti-inflammatory agents, but the anti-inflammatory mechanism remains to be established. We therefore investigated the anti-inflammatory effect of two purine analogues, MK118 bearing a nitrate ester moiety and the methyl-substituted analogue MK196 in Aortic Smooth Muscle Cells (AoSMCs), with emphasis on IL-1β release. The AoSMCs were stimulated with LPS with or without purine analogue, followed by ELISA, Olink proteomics, Western blot and real time PCR of NLRP3 inflammasome components. Both purine analogues inhibited the release of proteins involved in inflammation, such as TRAIL, CCL4, CSF1 and IL-1β in AoSMCs, as well as intracellular gene and protein expression of IL-1β and NLRP3 inflammasome components. MK196, but not MK118, also inhibited the LPS-induced release of IL-7, CXCL10, PD-L1, FLT3L and CCL20. We also showed that MK118 and possibly MK196 act via inhibition of JAKs. In silico studies showed that the purine moiety is a competent hinge binding motif and that the purine-piperazine scaffold is well accommodated in the lipophilic groove of JAK1-3. Both compounds establish interactions with catalytic amino acids in the active site of JAK1-3 and the terminal nitrate ester of MK118 was revealed as a promising pharmacophore.Our data suggest that MK118 and MK196 inhibit the release of proinflammatory proteins in AoSMCs, and targets JAK1-3 activation. Purine analogues also inhibit the expression of NLRP3 inflammasome genes and proteins and may in the future be evaluated for anti-inflammatory aspects on inflammatory diseases.

Are we there yet? Increasing use of cardioprotective antihyperglycemic agents in patients with T2D and CVD or CV risk in the United States

Objective To report on the use of antihyperglycemic agents (AHAs) by age (i.e. <65, ≥65 years) in patients with type 2 diabetes (T2D) and cardiovascular disease (CVD) or cardiovascular risk (CV risk) factors in the United States. Methods Patients with T2D and CVD (CVD cohort) or T2D and an additional CV risk factor without pre-existing CVD (CV risk cohort) were identified from 2015 to 2019 in a claims database. Patients were followed from their first observed CVD diagnosis or CV risk factor for each year they were continuously enrolled or until occurrence of a CVD diagnosis (CV risk cohort only). Classes of AHAs received were reported by year, cohort, and age group. Results From 2015 to 2019, the percentage of patients <65 years on glucagon-like peptide-1 receptor agonists (GLP-1 RAs) increased (CVD: 9–17%, CV risk: 9–17%) and was approximately twice that of those ≥65 years (CVD: 4–8%, CV risk: 4–8%); the percentage of patients <65 years on sodium-glucose cotransporter-2 (SGLT2) inhibitors increased (CVD: 11–16%, CV risk: 11–17%) and was approximately triple that of those ≥65 years (CVD: 3–6%, CV risk: 4–7%). Conclusions The use of GLP-1 RAs and SGLT2 inhibitors increased during the study period; however, most patients did not receive these medications. Patients aged ≥65 years were particularly disadvantaged.

Effect of Flavonoid Rich Fraction of Coriandrum sativum Leaf on Lipid Profile, Nitric Oxide, Ang II and Cardio Histopathology in L-NAME Intoxicated Experimental Rats

Coriandrum sativum has been used in traditional medicines as an anti-inflammatory, analgesic, and antibacterial agent. It is recently been shown to have antioxidant activities. This study evaluated the effects of Flavonoid Rich Fraction of Coriandrum sativum Leaf (FRFCSL) on Lipid Profile, Nitric Oxide, Ang II and Cardio Histopathology in L-NAME intoxicated Experimental Rats. Standard analytical method and DPPH radical scavenging activity were employed for the phytochemicals and antioxidant analysis respectively. The acute toxicity study showed the extract and flavonoids fraction are nontoxic at 5000mg/kg body weight. Thirty rats were divided into five groups of six (6) rats each. Group 1 was administered water and feed only, Group 2 was administered 40mg/kg N-Nitro-L-Arginine Methyl Ester (L-NAME) without treatment, Group 3 through 5 were administered 40mg/kg N-Nitro-L-Arginine Methyl Ester (L-NAME) with concomitant administration of Captopril (20mg/kg b.w), FRFCSL (200mg/kg b.w) and FRFCSL (400mg/kg b.w) respectively for 21 days. In phytochemical screening, presence of flavonoids, saponins, tannins, alkaloids, cardiac glycosides, steroids were confirmed as part of secondary metabolites in the extract. The flavonoid fraction showed increase % DPPH radical inhibition in concentration-dependent manner. FRFCSL treatment significantly (p&lt;0.05) and dose-dependently lowered low density lipoprotein and triglycerides. Also It significantly (p&lt;0.05) prevented L-NAME induced decrease in serum angiotensin II, high density lipoprotein and serum nitric oxide concentrations compared to the untreated rats. The Flavonoid Rich Fraction of Coriandrum Sativum Leaf showed great potential as antihypertensive, antihyperlipidemic and cardioprotective agent in rats thus confirming its usefulness in traditional health therapy and potential for antihypertensive drug development.

Discovery of 1,3,4-oxadiazole derivatives containing a bisamide moiety as a novel class of potential cardioprotective agents

Myocardial injury is a nonnegligible problem in cardiovascular diseases and cancer therapy. The functional feature of N-containing heterocycles in the cardiovascular field has attracted much attention in recent years. Herein, we discovered a lead compound 12a containing 1,3,4-oxadiazole by extensive screening of anticancer derivatives containing nitrogen-heterocycle, which exhibited potential protective activity against oxidative stress in cardiomyocytes. Follow-up structure-activity relationship (SAR) studies also highlighted the role of substitution sites and bisamide moiety in enhancing the protective activity against oxidative stress. Specifically, compound 12d exhibited low cytotoxicity under high concentration and potent myocardial protection against oxidative stress in H9c2 cells. Preliminary mechanistic studies showed compound 12d could decrease the expression of cardiac hypertrophy and oxidative stress-related proteins/genes and reduce mitochondria-mediated cell apoptosis, thereby enhancing the cell vitality of injured cardiomyocytes. In this study, 1,3,4-oxadiazole may represent a novel pharmacophore that possesses potential myocardial protection and provides more choices for future optimization of cardiovascular drugs, especially for the treatment of onco-cardiology.

Protective Effects of Amauroderma rugosum on Doxorubicin-Induced Cardiotoxicity through Suppressing Oxidative Stress, Mitochondrial Dysfunction, Apoptosis, and Activating Akt/mTOR and Nrf2/HO-1 Signaling Pathways.

Clinical outcomes for doxorubicin (Dox) are limited by its cardiotoxicity but a combination of Dox and agents with cardioprotective activities is an effective strategy to improve its therapeutic outcome. Natural products provide abundant resources to search for novel cardioprotective agents. Ganoderma lucidum (GL) is the most well-known edible mushroom within the Ganodermataceae family. It is commonly used in traditional Chinese medicine or as a healthcare product. Amauroderma rugosum (AR) is another genus of mushroom from the Ganodermataceae family, but its pharmacological activity and medicinal value have rarely been reported. In the present study, the cardioprotective effects of the AR water extract against Dox-induced cardiotoxicity were studied in vitro and in vivo. Results showed that both the AR and GL extracts could potentiate the anticancer effect of Dox. The AR extract significantly decreased the oxidative stress, mitochondrial dysfunction, and apoptosis seen in Dox-treated H9c2 rat cardiomyocytes. However, knockdown of Nrf2 by siRNA abolished the protective effects of AR in these cells. In addition, Dox upregulated the expression of proapoptotic proteins and downregulated the Akt/mTOR and Nrf2/HO-1 signaling pathways, and these effects could be reversed by the AR extract. Consistently, the AR extract significantly prolonged survival time, reversed weight loss, and reduced cardiac dysfunction in Dox-treated mice. In addition, oxidative stress and apoptosis were suppressed, while Nrf2 and HO-1 expressions were elevated in the heart tissues of Dox-treated mice after treatment with the AR extract. However, the GL extract had less cardioprotective effect against Dox in both the cell and animal models. In conclusion, the AR water extract demonstrated a remarkable cardioprotective effect against Dox-induced cardiotoxicity. One of the possible mechanisms for this effect was the upregulation of the mTOR/Akt and Nrf2/HO-1-dependent pathways, which may reduce oxidative stress, mitochondrial dysfunction, and cardiomyocyte apoptosis. These findings suggested that AR may be beneficial for the heart, especially in patients receiving Dox-based chemotherapy.

A nutraceutical combination of spirulina, reishi and moringa exerts significant cytoprotective effects againts doxorubicin and trastuzumab cardiotoxicity.

e24056 Background: Anthracycline and trastuzumab are essential adjuvant therapies for a variety of cancers, particularly breast, and gastric and esophageal cancers. Whilst prolonging cancer-related survival, these agents can induce drug-related cardiotoxicity. Cardioprotective agents used to mitigate cardiotoxicity, such as angiotensin antagonists, angiotensin receptor blockers and beta‐blockers, are often poorly tolerated in these patients due to intravascular volume fluctuations, which are further escalated by the hemodynamic side effects of these agents. Spiruline, Reishi and Moringa are nutaceuticals with anti-inflammatory effects that are currently used in cancer patients to improve quality of life and fatigue. We hypothesize that the combination of Spirulina, Reishi and Moringa could reduce inflammation and cardiotoxicity of anthracyclines and trastuzumab. Methods: Human cardiomyocytes were exposed to subclinical concentration of doxorubicin and trastuzumab (200 nM) alone or in combination with a formulation composed by Spiruline, Reishi and Moringa (at 10, 25 and 50 µg/ml) for 48h. Cell viability, apoptosis and necrosis were performed. Quantification of malondialdehyde and intracellular Ca2+ were performed through spectrophotometric methods. Anti-inflammatory studies were also performed (expression of NLRP3, TLR4/MyD88 pathways, nuclear expression of NF-kB). Intracellular concentration of IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL17-α were also performed. Results: Spiruline, Reishi and Moringa in combination increased synergistically the cell viability during exposure to doxorubicin and trastuzumab. The nutraceutical formulation reduces intracellular Ca2+ overload (-48,8% vs cells treated only to anticancer drugs; p &lt; 0,001), lipid peroxidation (- 47,2 % compared to cells exposed only to anticancer drugs; p &lt; 0,001). The expression of MyD88 and NLRP3 inflammasome were also reduced (-36,3 and -28,58 % vs cells exposed only to anticancer drugs, respectively; p &lt; 0.001). Notably, Spiruline, Reishi and Moringa increased of 26,3% the production of IL-10 and IL-2. Cytokines involved in cardiotoxicity and chemoresistance were reduced, such as IL-1α and IL-1β (-18,3 and -27,4 % vs DOXO-TRA group), IL-6 (-31,2 % vs DOXO-TRA group) and IL17-α (-27,3 % vs DOXO-TRA group) (p &lt; 0.01 for all). Conclusions: During exposure to doxorubicin and trastuzumab, the combination of Spiruline, Reishi and Moringa exerts cardioprotective and anti-inflammatory effects. Their properties are mediated by the reduction of iCa2+ content that consequently reduces lipid peroxidation and the expression of NLRP3- MyD88. These results indicating the potential use of this nutraceutical formulation in preclinical models of anthracycline and anti HER2 antibodies-mediated cardiotoxicity.

Large-scale evidence generation and evaluation across a network of databases for type 2 diabetes mellitus (LEGEND-T2DM): a protocol for a series of multinational, real-world comparative cardiovascular effectiveness and safety studies

IntroductionTherapeutic options for type 2 diabetes mellitus (T2DM) have expanded over the last decade with the emergence of cardioprotective novel agents, but without such data for older drugs, leaving a...

B-adrenergic/cAMP signaling in doxorubicin-induced cardiotoxicity

Doxorubicin (Dox) is one of the most commonly used chemotherapy but also one of the most cardiotoxic. As of today, only the iron chelator Dexrazoxane has been FDA and EMA approved as a cardioprotective agent for Dox but its usage is still controversial. Thus, there is an urgent need to identify new targets to develop an effective protection against Dox-induced cardiotoxicity (DIC) without compromising its anti-tumor action. Well-characterized DIC mechanisms include topoisomerase II inhibition, DNA damages, induction of ROS and bioenergetic distress that lead to cardiomyocyte death. Alternative mechanisms are emerging such as an alteration of the β-adrenergic system. Our objective here was to study DIC mechanisms with a specific focus on how Dox treatment affects the β-adrenergic/cAMP signaling cascade. We used FRET-based sensors for cAMP targeted to two different cellular compartments, cytosol and nucleus, and measured the cAMP response to the β-adrenergic agonist isoprenaline (Iso, 10 nM) in adult rat ventricular myocytes after 24 h treatment with 1 or 10 μM Dox. Basal cAMP concentration was measured by Elisa. Adenylyl cyclase (AC5 and AC6 isoforms) mRNA was measured by RT-qPCR and phosphodiesterase (PDE) isoform expression and activity by western blot and radioenzymatic assay, respectively. cAMP response to Iso was decreased by 25% at 1 μM and > 50% at 10 μM Dox in both cytosol and nucleus. The maximal response to 20 μM L858051 (a forskolin analog) + 200 μM IBMX (a PDE inhibitor) on top of Iso was also decreased by Dox. Dox treatment did not change basal cAMP level nor PDE activity, but decreased AC5 and AC6 mRNA and PDE4 protein expression. Doxorubicin treatment downregulates the β-adrenergic/cAMP cascade in ventricular myocytes by decreasing adenylyl cyclase expression and maximal activity. This may contribute to the Dox-induced cardiotoxicity mechanisms.

Comparisons of pleiotropic effects of SGLT2 inhibition and GLP-1 agonism on cardiac glucose intolerance in heart dysfunction.

Recent studies discuss the evidence of lesser degrees of hyperglycemia contribution to cardiovascular disease (CVD) than impaired glucose tolerance. Indeed, the biggest risk for CVD seems to shift to glucose intolerance in humans with insulin resistance. Although there is a connection between abnormal insulin signaling and heart dysfunction in diabetics, there is also a relation between cardiac insulin resistance and aging heart failure (HF). Moreover, studies have revealed that HF is associated with generalized insulin resistance. Recent clinical outcomes parallel to the experimental data undertaken with antihyperglycemic drugs have shown their beneficial effects on the cardiovascular system through a direct effect on the myocardium, beyond their ability to lower blood glucose levels and their receptor-associated actions. In this regard, several new-class drugs, such as glucagon-like peptide 1 receptor agonists (GLP-1Ra) and sodium-glucose cotransport 2 inhibitors (SGLT2i), can improve cardiac health beyond their ability to control glycemia. In recent years, great improvements have been made toward the possibility of direct heart-targeting effects including modulation of the expression of specific cardiac genes in vivo for therapeutic purposes. However, many questions remain unanswered, regarding their therapeutic effects on cardiomyocytes in heart failure, although there are various cellular levels studies with these drugs. There are also some important comparative studies on the role of SGLT2i versus GLP-1Ra in patients with and without CVD as well as with or without hyperglycemia. Here, we sought to summarize and interpret the available evidence from clinical studies focusing on the effects of either GLP-1Ra or SGLT-2i or their combinations on cardiac structure and function. Furthermore, we documented data from experimental studies, at systemic, organ, and cellular levels. Overall, one can summarize that both clinical and experimental data support that either SGLT2i or GLP-1R agonists have similar benefits as cardioprotective agents in patients with or without impaired glucose tolerance.

Design, synthesis, and in vitro protective effect evaluation of α-carboline derivatives against H2O2-induced cardiomyocyte injury

As one of the most important features of myocardial ischemia reperfusion (MI/R) injury, the overproduction of reactive oxygen species (ROS) overwhelms the intrinsic antioxidant and impairs the function of mitochondria and, finally, leads to cardiomyocyte death. To improve the damage of cardiomyocyte caused by oxidative stress, a series of α-carboline derivatives were designed and synthesized in this study. The biological studies revealed that most of the α-carbolines exhibited obvious protective activities against H2O2-induced cardiomyocyte injury. Among them, compound 14b significantly increased the cell viability in H2O2-induced oxidative stress in H9c2 cardiomyoblasts with a concentration-dependent manner, which was more potent than polydatin. Pretreatment of 14b obviously inhibited H2O2-induced lactate dehydrogenase (LDH) leakage, enhanced the capacity of endogenous antioxidant defenses, including superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and reduced the formation of the toxic product of lipid peroxidation (malondialdehyde, MDA). In addition, 14b effectively reduced the overproduction of ROS and restored the mitochondrial membrane potential ΔΨm, better than that of polydatin. Flow cytometry analysis demonstrated that 14b markedly reduced both necrosis and apoptosis in H9c2 cells after the exposure to H2O2. Further Western blot analysis revealed that 14b obviously decreased the ratio of Bax/Bcl-2 and reduced the expression of cytochrome c. Overall, these results revealed the potential of α-carboline 14b as a promising cardioprotective agent against H2O2-induced oxidative injury.