Cardioprotective Effects Research Articles

SGLT2 inhibitor downregulates ANGPTL4 to mitigate pathological aging of cardiomyocytes induced by type 2 diabetes

BackgroundSenescence is recognized as a principal risk factor for cardiovascular diseases, with a significant association between the senescence of cardiomyocytes and inferior cardiac function. Furthermore, type 2 diabetes exacerbates this aging process. Sodium-glucose co-transporter 2 inhibitor (SGLT2i) has well-established cardiovascular benefits and, in recent years, has been posited to possess anti-aging properties. However, there are no reported data on their improvement of cardiomyocytes function through the alleviation of aging. Consequently, our study aims to investigate the mechanism by which SGLT2i exerts anti-aging and protective effects at the cardiac level through its action on the FOXO1-ANGPTL4 pathway.MethodsTo elucidate the underlying functions and mechanisms, we established both in vivo and in vitro disease models, utilizing mice with diabetic cardiomyopathy (DCM) induced by type 2 diabetes mellitus (T2DM) through high-fat diet combined with streptozotocin (STZ) administration, and AC16 human cardiomyocyte cell subjected to stimulation with high glucose (HG) and palmitic acid (PA). These models were employed to assess the changes in the senescence phenotype of cardiomyocytes and cardiac function following treatment with SGLT2i. Concurrently, we identified ANGPTL4, a key factor contributing to senescence in DCM, using RNA sequencing (RNA-seq) technology and bioinformatics methods. We further clarified ANGPTL4 role in promoting pathological aging of cardiomyocytes induced by hyperglycemia and hyperlipidemia through knockdown and overexpression of the factor, as well as analyzed the impact of SGLT2i intervention on ANGPTL4 expression. Additionally, we utilized chromatin immunoprecipitation followed by quantitative real-time PCR (ChIP-qPCR) to confirm that FOXO1 is essential for the transcriptional activation of ANGPTL4.ResultsThe therapeutic intervention with SGLT2i alleviated the senescence phenotype in cardiomyocytes of the DCM mouse model constructed by high-fat feeding combined with STZ, as well as in the AC16 model stimulated by HG and PA, while also improving cardiac function in DCM mice. We observed that the knockdown of ANGPTL4, a key senescence-promoting factor in DCM identified through RNA-seq technology and bioinformatics, mitigated the senescence of cardiomyocytes, whereas overexpression of ANGPTL4 exacerbated it. Moreover, SGLT2i improved the senescence phenotype by suppressing the overexpression of ANGPTL4. In fact, we discovered that SGLT2i exert their effects by regulating the upstream transcription factor FOXO1 of ANGPTL4. Under conditions of hyperglycemia and hyperlipidemia, compared to the control group without FOXO1, the overexpression of FOXO1 in conjunction with SGLT2i intervention significantly reduced both ANGPTL4 mRNA and protein levels. This suggests that the FOXO1-ANGPTL4 axis may be a potential target for the cardioprotective effects of SGLT2i.ConclusionsCollectively, our study demonstrates that SGLT2i ameliorate the pathological aging of cardiomyocytes induced by a high glucose and high fat metabolic milieu by regulating the interaction between FOXO1 and ANGPTL4, thereby suppressing the transcriptional synthesis of the latter, and consequently restoring cardiac function.Graphical abstract

Resveratrol alleviates heart failure by activating foxo3a to counteract oxidative stress and apoptosis

Resveratrol has been extensively studied for its multifaceted health benefits. Nonetheless, the pharmacological mechanisms of resveratrol for heart failure remain elusive, especially the cardioprotective effects. To address this knowledge gap, we performed high-throughput drug screening using zebrafish and discovered that resveratrol significantly alleviated heart failure, including rescuing abnormalities in heart rate, blood flow, cardiac output, and nppb overexpression. Mechanically, calcium optical mapping revealed that resveratrol diminished the prolongation of calcium duration at 90 % repolarization (CaD90). Membrane potential assay demonstrated that resveratrol alleviated mitochondrial damage, subsequently relieved the excessive accumulation of reactive oxygen species (ROS). Tunel staining further showed that resveratrol inhibited cardiomyocyte apoptosis both in zebrafish and human AC16 cell. Given the close relationship between the Forkhead Box O (foxo) family and oxidative stress and apoptosis, we used qPCR and noted that resveratrol could regulate the heart failure-induced expressions of foxo1b and foxo3a to normal levels. Furthermore, we conducted in situ hybridization to confirm the effective down-regulation patterns of foxo3a after resveratrol treatment. To investigate whether resveratrol’s effects are mediated via foxo3a, we used gardenoside to inhibit foxo3a expression, noting that resveratrol’s cardioprotective effects were reduced with foxo3a inhibition. Overall, our study underscores the molecular mechanisms by which resveratrol confers cardioprotection and provides a reference for heart failure therapeutic approaches.

Oleoylethanolamide mitigates cardiometabolic disruption secondary to obesity induced by high-fat diet in mice

Chronic lipid overnutrition has been demonstrated to promote cardiac dysfunction resulting from metabolic derangement, inflammation, and fibrosis. Oleoylethanolamide (OEA), an endogenous peroxisome proliferator activating receptor (PPAR)-α agonist, has been extensively studied for its metabolic properties.The aim of this study was to determine if OEA has beneficial effects on high-fat diet (HFD)-induced cardiac disruption in obese mice, focusing on the underlying pathological mechanisms.OEA treatment restores the metabolic pattern, improving serum glycaemic and lipid profile. OEA also reduces heart weight and serum creatine kinase-myocardial band (CK-MB), a marker of cardiac damage. Accordingly, OEA modulates cardiac metabolism, increasing insulin signaling and reducing lipid accumulation. OEA increases AMPK and AKT phosphorylation, converging in the rise of AS160 activation and glucose transporter (GLUT)4 protein level. Moreover, OEA reduces the transcription of the cardiac fatty acid transporter CD36 and fatty acid synthase and increases PPAR-α mRNA levels. Adiponectin and meteorite-like protein transcription levels were significantly reduced by OEA in HFD mice, as well as those of inflammatory cytokines and pro-fibrotic markers. An increased autophagic process was also shown, contributing to OEA's cardioprotective effects. Metabolomic analyses of cardiac tissue revealed the modulation of different lipids, including triglycerides, glycerophospholipids and sphingomyelins by OEA treatment. In vitro experiments on HL-1 cardiomyocytes showed OEA's capability in reducing inflammation and fibrosis following palmitate challenge, demonstrating a direct activity of OEA on cardiac cells, mainly mediated by PPAR-α activation.Our results indicate OEA as a potential therapeutic to restrain cardiac damage associated with metabolic disorders.

Pharmacological Attributes of Hesperidin

: Hesperidin is a major flavonoid in sweet oranges and lemons. Aglycone form of hesperidin i.e., hesperetin, and their various derivatives possess significant potential as therapeutic agents for a wide range of diseases and disorders. No signs of toxicity have been observed with the normal intake of hesperidin or related compounds. Hesperidin has been reported to possess a wide range of pharmacological properties, which includes antioxidant, anti-viral, anticancer, antidiabetic, analgesic, organ protective, neuroprotective, antihypertensive, and cardioprotective effects. This needs to be effectively studied at the clinical level so as to firmly establish the usefulness of these compounds in the treatment or prevention of disease in humans. This paper reviews various aspects of hesperidin, including their chemistry, biosynthesis, and bioactivity.

Therapeutic Potential of Syzygium aromaticum in Gut Dysbiosis via TMAO Associated Diabetic Cardiomyopathy.

Dysbiosis of the gastrointestinal microbiota is not only related to the pathogenesis of intestinal disorders but also associated with extra-intestinal diseases. Various studies have revealed the role of an imbalance of intestinal microbiota and their metabolites including bile acids, indole derivatives, polyamines, and trimethylamine in the progression of various diseases. The elevated plasma level of the oxidized form of trimethylamine is associated with the increased risk of cardiovascular diseases. Literature supports that herbal medicines can modulate human health by altering the diversity of gut microbiota and their metabolites and proposes the use of prebiotics to improve dysbiotic conditions as a new way of therapeutic strategy. In silico studies including drug likeliness, toxicity prediction, and molecular interaction of phytochemicals against trimethylamine lyase enzyme have been done. Antimicrobial activity of extracts of selected plant i.e. Syzygium aromaticum was done by disc diffusion and the protective effects of plant compounds were examined on trimethylamine-n-oxide a bacterial metabolic product and high glucose induced toxicity. The current study has found that the phytochemicals of S. aromaticum identified as nontoxic and followed the standard rules of drug likeliness and showed a significant binding affinity against trimethylamine-n-oxide producing enzymes. Furthermore, S. aromaticum extract was found to have antimicrobial potential and cardioprotective effects by reducing the production of intracellular reactive oxygen species and correcting the distorted nuclear morphology in the presence of high trimethylamine-n-oxide. Conclusively, our study explored the herbal intervention in intestinal dysbiosis and suggested a natural therapy against dysbiosis associated with cardiac disease, and S, aromaticum was found to have exceptional cardioprotective potential against TMAO induced gut dysbiosis, which provides a novel future therapeutic intervention for treating cardiovascular complications.

Effect of lipoic acid on cisplatin-induced cardiotoxicity and inflammation in cardiomyocytes

Aims: Cisplatin (CPL) is a potent chemotherapeutic agent widely used to treat various cancers. However, CPL causes toxicity in various tissues, including the heart. Lipoic acid (LPA) is a thiol compound with antioxidant, anti-inflammatory, and antiapoptotic properties. Although LPA has been reported to have protective effects in various cardiac diseases, the mechanisms underlying its cardio-protective effects have not been elucidated. This study aimed to establish a CPL-induced cardiotoxicity model in the H9c2 cardiomyocyte cell line, to understand the mechanisms underlying this cardiotoxicity, and to investigate the effect of LPA on cardiotoxicity. Methods: H9c2 cardiomyocyte cells as control (CNT), CPL (40 µm), and LPA-1 (300 µm LPA, and 40 µm CPL), LPA-2 (500 µm LPA, and 40 µm CPL) in combination along with CIS were used. In the analyses made, glutathione (GSH) and glutathione peroxidase (GSHPx) enzyme activity, lipid peroxidation [malondialdehyde, (MDA)] levels, inflammation markers interleukin (IL) -1ß, IL-6, and tumor necrosis factor (TNF) -? levels, total oxidant/antioxidant (TOS and TAS) status levels, reactive oxygen species (ROS) and caspase activity (Casp 3 and 9) in the cells were determined. Results: CIS treatment caused cardiomyocyte cell toxicity and increased Casp 3, Casp 9, ROS, IL-1ß, IL-6, TNF-?, TOS, and MDA levels while decreasing GSHPx, GSH, and TAS levels. Increased inflammation and impaired oxidant/antioxidant balance in cardiomyocyte cells after CPL treatment were regulated by LPA treatment. Conclusion: LPA treatment was found to have a protective effect against CPL-induced cardiotoxicity in cardiomyocyte cells.

PDE4B abrogation extenuates angiotensin II-induced endothelial dysfunction related to hypertension through up-regulation of AMPK/Sirt1/Nrf2/ARE signaling.

Endothelial dysfunction is commonly perceived as a precursor in the process of hypertension, a severe cardiovascular disorder. Phosphodiesterase 4B (PDE4B) inactivation has been proposed to exert cardioprotective effects and prevent pulmonary hypertension. However, the role of PDE4B in endothelial dysfunction in hypertension remains inexplicit, which will be investigated in the present work. In angiotensin II (Ang II)-induced human umbilical vein endothelial cells (HUVECs), RT-qPCR and Western blotting were used to analyze PDE4B expression. CCK-8 method was used to detect cell viability. Flow cytometry assay and Caspase 3 assay kit were used to detect cellular apoptotic level. Wound healing and tube formation assays were respectively used to detect cell migration and angiogenesis. Western blotting and corresponding assay kits were respectively used to analyze the expressions and contents of endothelial dysfunction markers. JC-1 assay, RT-qPCR and relevant assay kit were respectively used to detect mitochondrial membrane potential (ΔΨm), quantify mitochondrial DNA (mtDNA) copy number and mitochondrial permeability transition pore (mPTP) opening. Besides, Western blotting was used to analyze the expressions of endoplasmic reticulum stress (ERS) and AMP-activated protein kinase (AMPK)/sirtuin 1 (Sirt1)/nuclear factor-erythroid 2 related factor 2 (Nrf2)/antioxidant response element (ARE) signaling-associated proteins. PDE4B expression was increased in Ang II- induced HUVECs. PDE4B knockdown promoted the viability, migration, angiogenesis while inhibiting the apoptosis, endothelial dysfunction, ERS and mitochondrial damage in Ang II-induced HUVECs. Additionally, PDE4B silence activated AMPK/Sirt1/Nrf2/ARE pathway and AMPK inhibitor Compound C (CC) partially reversed the effects of PDE4B down-regulation on Ang II-induced HUVECs. Conclusively, PDE4B inhibition might protect against Ang II-induced endothelial dysfunction in HUVECs via up-regulating AMPK/Sirt1/Nrf2/ARE pathway, which might be mediated by the suppression of ERS and mitochondrial damage.

Comparison between the ECG Outcomes of Metoprolol and Bisoprolol.

Beta-blockers are essential agents in the management of cardiovascular diseases, such as heart failure, acute myocardial infarction (MI), and cardiac arrhythmias. However, there are diurnal variations in the cardioprotective effects of the subgroups as a result of their different pharmacokinetic, pharmacodynamic, and pharmacogenetic profiles. We aimed to compare metoprolol and bisoprolol in terms of electrocardiogram (ECG) outcomes. A retrospective cross-sectional study was conducted at Prince Sultan Cardiac Center. The trial included 404 patients who met the inclusion criteria (204 in the metoprolol arm and 200 in the bisoprolol arm). Using case record forms that had already been created, information, such as patient demographics, medical histories, and treatment histories, was taken from their medical files. The most recent ECG records were also gathered. The ethical approval for this study was obtained from Qassim ethical committee (approval number: 45-44-902). There was no significant difference found between the patients in both arms in terms of baseline characteristics, age, or sex. In this retrospective cross-sectional study, we have compared the effects of metoprolol and bisoprolol beta blockers on ECG changes. The findings have indicated no difference between metoprolol and bisoprolol groups in terms of all ECG readings, particularly PR/ms, QTC-ms, and ventricular rate. Further studies are required to confirm these findings.

The sodium/glucose cotransporter 2 inhibitor Empagliflozin inhibits long QT 3 late sodium currents in a mutation specific manner

BackgroundSodium/glucose cotransporter 2 inhibitors (SGLT2is) like empagliflozin have demonstrated cardioprotective effects in patients with or without diabetes. SGLT2is have been shown to selectively inhibit the late component of cardiac sodium current (late INa). Induction of late INa is the primary mechanism in the pathophysiology of congenital long QT syndrome type 3 (LQT3) gain-of-function mutations in the SCN5A gene encoding Nav1.5. We investigated empagliflozin's effect on late INa in thirteen known LQT3 mutations located in distinct regions of the channel. MethodsThe whole-cell patch-clamp technique was used to investigate the effect of empagliflozin on late INa in recombinantly expressed Nav1.5 channels containing different LQT3 mutations. Molecular modeling of human Nav1.5 and simulations in a mathematical model of human ventricular myocytes were used to extrapolate our experimental results to excitation-contraction coupling. ResultsEmpagliflozin selectively inhibited late INa in LQT3 mutations in the inactivation gate region of Nav1.5, without affecting peak current or channel kinetics. In contrast, empagliflozin inhibited both peak and late INa in mutations in the S4 voltage-sensing regions, altered channel gating, and slowed recovery from inactivation. Empagliflozin had no effect on late/peak INa or channel kinetics in channels with mutations in the putative empagliflozin binding region. Simulation results predict that empagliflozin may have a desirable therapeutic effect in LQT3 mutations in the inactivation gate region. ConclusionsEmpagliflozin selectively inhibits late INa, without affecting channel kinetics, in LQT3 mutations in the inactivation gate region. Empagliflozin may thus be a promising precision medicine approach for patients with specific LQT3 mutations.

Transcutaneous auricular vagus nerve stimulation attenuates stroke-heart syndrome: The role of parasympathetic activity

Stroke induces cardiac dysfunction, which increases poststroke mortality and morbidity. An imbalance in the autonomic nervous system resulting from brain injury may serve as the underlying mechanism. The present study investigated whether transcutaneous auricular vagus nerve stimulation (taVNS) attenuates poststroke cardiac dysfunction by activating the parasympathetic nervous system. Adult male mice were subjected to transient middle cerebral artery occlusion (MCAO) and reperfusion surgery. The mice in the treatment group received repeated taVNS starting 60 min after the onset of cerebral ischemia. To assess whether the effects of taVNS were associated with parasympathetic activity, the MCAO mice in the atropine group received intraperitoneal injections of atropine to inhibit parasympathetic activity prior to taVNS. taVNS significantly increased the left ventricular ejection fraction (EF), attenuated myocardial apoptosis, reduced myocardial hypertrophy, and reduced fibrosis following stroke. The beneficial effects of taVNS on cardiac dysfunction were abolished by atropine administration. Heart rate variability (HRV) analysis and western blot analysis revealed that taVNS increased parasympathetic activity but decreased sympathetic dominance in mice with MCAO. Furthermore, the cardioprotective effects of taVNS were associated with muscarinic acetylcholine receptor activation, PI3K–Akt pathway modulation, and eNOS regulation in the heart. Therefore, taVNS alleviates cardiac dysfunction after stroke and is associated with activation of the parasympathetic nervous system.

Bag2 protects against doxorubicin-induced cardiotoxicity by maintaining Pink1-mediated mitophagy

The clinical application of Doxorubicin (DOX) is limited due to its cardiotoxicity. Mitophagy dysfunction is the primary cause of DOX-induced cardiotoxicity (DIC). However, the precise mechanism by which DOX regulates mitophagy remains elusive. Bag2 (BCL2-associated athanogene 2) is a cochaperone implicated in multiple pathological states. The aim of this study was to investigate the potential cardio-protective effects of Bag2 in DIC. C57BL/6 mice and AC16 cells were used to establish DIC model. The expression of Bag2 were measured by western blotting and immunohistochemical. The effects of Bag2 on DIC were assessed through functional gain and loss experiments. Through in vitro and in vivo experiments, we found that Bag2 expression was significantly reduced after DOX treatment. Both Bag2 knockdown and DOX administration resulted in apoptosis, mitochondrial dysfunction, and impaired mitophagy. Conversely, Bag2 overexpression exerted protective effects against these phenotypes induced by DOX stimulation. Mechanistically, Bag2 maintained mitophagy activation by binding to Pink1 and protecting it from proteasome-dependent degradation, thereby preserving mitochondrial function and protecting against myocardial lesions. Our findings suggest that Bag2 may serve as a promising therapeutic target for the treatment of DIC.

A Review of the Phytochemical and Pharmacological Properties of Aegle marmelos Plants

Aegle marmelos (L.), commonly known as bael, is a medicinal plant widely used in traditional systems of medicine such as Ayurveda for its numerous therapeutic properties. This review provides an overview of the phytochemical and pharmacological properties of Aegle marmelos across various parts of the plant, including its leaves, fruit, roots, and bark. Phytochemical studies have revealed the presence of a wide variety of bioactive compounds such as alkaloids, flavonoids, tannins, and coumarins, which contribute to its diverse medicinal benefits. The plant has demonstrated various pharmacological activities in both in vitro and in vivo studies, including antioxidant, anti-inflammatory, antimicrobial, antidiabetic, hepatoprotective, cardioprotective, and anticancer properties. The antioxidant potential of Aegle marmelos is attributed to its high content of phenolic compounds, which help in scavenging free radicals and reducing oxidative stress. Additionally, its antiinflammatory activity makes it useful for treating conditions related to inflammation and infection. Its hepatoprotective and cardioprotective effects further underline its potential in safeguarding liver and heart health. Despite its wide traditional use, further clinical studies are needed to validate these pharmacological claims and explore its potential applications in modern medicine. This review aims to consolidate existing knowledge on the therapeutic properties of Aegle marmelos, thereby encouraging further research into its medicinal value and potential pharmaceutical applications.

Cardioprotective effects of S-equol, a soybean metabolite with estrogen activity, and role of the PI3K/Akt pathway in a male rat model of ischemic reperfusion

PurposeS-equol, an isoflavone metabolite with high estrogenic activity, exhibits organ-protective effects via the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. While estrogen has cardioprotective effects against ischemia–reperfusion injury, whether S-equol shares this capability remains uncertain. This study aimed to assess the cardioprotective effects of S-equol on stunned myocardium using an isolated rat heart model and investigate the involvement of PI3K/Akt signaling pathway. MethodsMale rat hearts were perfused using the Langendorff system and divided into four groups: 1) modified Krebs–Henseleit (KH) buffer containing 1 μmol/L S-equol (EQ); 2) KH buffer (Cont); 3) KH buffer supplemented with 1 μmol/L S-equol and 100 nmol/L wortmannin (a specific PI3K inhibitor) (EQW); or 4) KH buffer containing wortmannin (ContW). After stabilization, each group was perfused for 20 min before undergoing 7.5 min of no-flow ischemia, followed by 20 min reperfusion. The primary outcome was the maximum left ventricular derivative of pressure development (left ventricle [LV] dP/dt max)after 20 min of reperfusion. Myocardial Akt and glycogen synthase kinase-3 beta (GSK-3β) were assayed using western blotting. ResultsLV dP/dt max was greater in the EQ group than that in the Cont group after 15 and 20 min of reperfusion; however, this effect was attenuated in the presence of PI3K inhibitors. S-equol treatment increased Akt and suppressed GSK-3β expression in the EQ group compared to that in the Cont group. However, these effects were not observed in the presence of wortmannin. ConclusionS-equol exerts a protective effect against myocardial ischemia–reperfusion injury, possibly by activating PI3K/Akt signaling.

The effect of a new product based on quercetin and a thick extract of carrot seed root on the histological state of the rat cardiac muscle in the adrenaline-hydrocortisone-induced myocardial infarction

Aim. To study the effect of tablets with a thick extract of carrot seed root and quercetin on the histological state of the rat cardiac muscle in the experimental adrenaline-hydrocortisone-induced myocardial infarction. Materials and methods. The cardioprotective effect of tablets with a thick extract of carrot seed root and quercetin was studied on the model of acute adrenaline-hydrocortisone-induced myocardial infarction caused by subcutaneous administration of 0.1 % adrenaline hydrochloride solution in the dose of 1 mg/kg and 2.5 % hydrocortisone acetate emulsion in the dose of 12.5 mg/kg of the animal weight twice daily for a week. The tablets under research in the dose of 200 mg/kg and the reference drugs – “Thiotriazolin” and “Cratal” tablets were administered for 14 days – 7 days before the infarction modeling and 7 days of the myocardial infarction development, after which their effect on the histological state of the rat heart muscle was studied. Results. Modeling of the adrenaline-hydrocortisone-induced myocardial infarction in rats is accompanied by the appearance of focal necrotic changes in muscle cells, which in some cases are accompanied by initial regenerative manifestations in the form of granuloma formation; dystrophic processes of cardiomyocytes. The therapeutic and prophylactic administration of tablets from a thick extract of carrot seed root and quercetin on the model of the adrenaline-hydrocortisone-induced myocardial infarction has the cardioprotective effect, reducing the severity of necrotic and dystrophic changes in the cardiac muscle. Conclusions. As a result of modeling of the adrenaline-hydrocortisone-induced myocardial infarction in rats, focal necrotic changes in muscle cells were observed, sometimes accompanied by the initial formation of a matrix consisting of young fibroblasts; dystrophic processes of cardiomyocytes, in particular myocytolysis, fluctuations in the size of nuclei. The therapeutic and preventive administration of the tablets studied on the model of the adrenaline-hydrocortisone-induced myocardial infarction has the cardioprotective effect, reduces the severity of necrotic and dystrophic changes in the cardiac muscle. By the cardioprotective effect expressiveness, tablets with a thick extract of carrot seed root and quercetin on the model of the adrenaline-hydrocortisone-induced myocardial infarction are not inferior to the reference drugs – “Thiotriazolin” and “Cratal” tablets. The results experimentally substantiate the feasibility of creating a new combined drug from a thick extract of carrot seed root and quercetin for the prevention and pharmacocorrection of a cardiovascular pathology.

Empagliflozin improves pressure-overload-induced cardiac hypertrophy by inhibiting the canonical Wnt/β-catenin signaling pathway

BackgroundEmpagliflozin (EMPA) is an SGLT-2 inhibitor that can control hyperglycemia. Clinical trials have indicated its cardio-protective effects against cardiac remodeling in diabetes or non-diabetes patients. However, the underlying molecular mechanisms of EMPA’s cardio-protective effects remain elusive.MethodsWe evaluated whether the EMPA attenuated the pressure-overload-induced cardiac hypertrophy by inhibiting the Wnt/β-catenin pathway. Furthermore, the effects of the EMPA on a mouse model of transverse aortic constriction (TAC) induced cardiac hypertrophy was also evaluated. Mice were administrated with 0.5% CMC-Na as a vehicle or EMPA (10 mg/kg/day, daily, throughout the study) by intragastric gavage.ResultsThe in vivo echocardiography and histologic morphological analyses revealed that EMPA attenuated TAC-induced cardiac hypertrophy. Moreover, it also ameliorated TAC-induced cardiac fibrosis and decreased the cell size of the cardiomyocytes in isolated adult cardiomyocytes. Molecular mechanism analysis revealed that the EMPA reduced the TAC-induced enhanced expression of the Wnt/β-catenin pathway in vivo. For in vitro assessments, isolated neonatal rat cardiomyocytes (NRCMs) were treated with Angiotensin II (AngII) and EMPA; the results showed that in the absence of EMPA, the expression of the Wnt/β-catenin pathway was enhanced. In the trans-genetic heterozygous β-catenin deletion mice, EMPA attenuated TAC-induced cardiac remodeling by reducing the Wnt/β-catenin pathway. In addition, molecular docking analysis indicated that EMPA interacts with FZD4 to inhibit the TAC and AngII induced Wnt/β-catenin pathway in cardiomyocytes.ConclusionOur study illustrated that EMPA might directly interact with FZD4 to inhibit the TAC and AngII-induced activation of the Wnt/β-catenin pathway to attenuate the adverse cardiac remodeling.

The Medicinal Potential of Rosa centifolia L.: Integrating Botany, Geographical Distribution, Pharmacology, Ethnobotanical Uses, Phytochemistry, and Toxicology.

Rosa centifolia L. is widely used to treat various health issues such as digestive, respiratory, and cardiovascular ailments. This study aims to assess the ethnopharmacological, phytochemical, pharmacological, and toxicological research on R. centifolia, combining traditional knowledge with modern computational techniques. A literature survey from 2000 to 2024 using Science Direct, Web of Science, and Scopus identified relevant studies. Traditionally used in countries such as Morocco, China, India, and across Europe and Asia, Rosa centifolia L. contains compounds like alkaloids, glycosides, saponins, flavonoids, terpenoids, tannins, lignans, and steroids. Its extracts demonstrate various pharmacological activities, including anti-inflammatory, anti-HIV, antitussive, vasorelaxant, hepatoprotective, nephroprotective, antidepressant, antiulcer, immunostimulatory, cardioprotective, antimicrobial, and antioxidant effects. This work provides a comprehensive understanding of Rosa centifolia's therapeutic potential, chemical composition, and safety profile, highlighting its significant potential for treating various diseases and warranting further research.

Combined Bisoprolol and Trimetazidine ameliorate Arsenic trioxide -Induced Acute Myocardial Injury in Rats: Targeting PI3K/GSK-3β/Nrf2/HO-1 and NF-κB/iNOS Signaling Pathways, Inflammatory Mediators and Apoptosis

Background Arsenic-trioxide (ATO) is an effective therapy for acute promyelocytic leukemia. Unfortunately, its utility is hindered by the risk of myocardial injury. Both bisoprolol (BIS) and trimetazidine (TMZ) have various pharmacological features, including anti-oxidant, anti-inflammatory, and anti-apoptotic properties. Aim The cardioprotective effects of BIS and TMZ were studied, and their mechanistic role in ameliorating ATO-induced myocardial injury. Materials and Methods Forty male Wistar rats were randomly allotted into five groups as follows: normal control group (received normal saline, orally), ATO group (7.5 mg/kg, orally), BIS (8 mg/kg, orally), TMZ (60 mg/kg, orally), and finally combination group (BIS + TMZ + ATO). Following 21 days, samples of serum and cardiac tissues were obtained to perform biochemical, molecular, and histopathological investigations. Results The present study showed that ATO caused myocardial injury evidenced by changes in serum biomarkers (Aspatate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, creatine kinase-MB, and cardiac troponin-1), electrolyte imbalance, and lipid profiles alongside histopathologic changes. In addition, ATO administration significantly elevated malondialdehyde, nicotinamide adenine dinucleotide phosphate hydrogen oxidase, myloperoxidase, total nitrite, inducible nitric oxide synthase, tumor necrosis factor-alpha, interleukin-1β, interleukin-6, 8-Hydroxy-2'-deoxyguanosine, nuclear factor NF-kappa-B p65 subunit, glycogen synthase kinase-3 beta, and caspase-3 expression contemporaneously with down-regulation of reduced glutathione, glutathione peroxidase, superoxide dismutase, catalase, heme oxygenase 1, nuclear factor erythroid 2–related factor 2, phosphatidylinositol-3 kinase, p-PI3K, and Bcl-2 expression. Interestingly, pre-treatment with BIS and TMZ significantly reversed the detrimental effects of ATO-induced myocardial injury at both cellular and molecular levels. Otherwise, combining the two drugs displayed more enhancement than each drug alone. Conclusion The present research depicted that BIS and TMZ have the potential to protect the heart and provide therapeutic benefits by preventing acute heart injury induced by ATO. This is achieved by reversing the redox-sensitive pathway, reducing inflammation, and inhibiting apoptosis.

The Protective Effects of Carvacrol Against Doxorubicin-Induced Cardiotoxicity In Vitro and In Vivo.

Doxorubicin (DOX) is a remarkable chemotherapeutic agent, however, its adverse effect on DOX-induced cardiotoxicity (DIC) is a rising concern. Recent research has identified carvacrol (CAR), an antioxidant and anti-inflammatory agent, as a promising natural compound for protecting against DIC. This study aims to investigate the potential cardioprotective effects properties of CAR in vitro and in vivo. The cardioprotective effect of CAR was assessed by pretreating H9c2 cells with non-toxic CAR for 24h, followed by co-treatment with DOX (10μM) for an additional 24h. The cell viability was determined using an MTT assay. For the in vivo study, male Sprague-Dawley rats (200-250g) were randomly divided into three groups: control, cardiotoxicity (DOX), and treatment (CAR + DOX) groups. CAR (50mg/kg, BW) was administered orally to the CAR + DOX groups for 14days. Then, a single dose of DOX (15mg/kg/i.p, BW) was administered on day 15 for DOX and CAR + DOX groups. The rats were allowed to recover for 3days before being sacrificed. Our results demonstrated that DOX (10µM) significantly reduced H9c2 cell viability by 50% (p < 0.0001), and CAR (0.067µM) protected H9c2 cells from DIC (p = 0.0045). In the rat model, CAR pretreatment effectively mitigated DOX-induced reductions in systolic pressure (p = 0.0007), pulse pressure (p = 0.0213), hypertrophy (p = 0.0049), and cardiac fibrosis (p = 0.0006). However, the pretreatment did not alter the heart function, oxidative stress, and antioxidant enzymes. In conclusion, our results indicate that CAR could potentially serve as an adjuvant to reduce cardiotoxicity by ameliorating myocardial fibrosis and hypertrophy.

Andrographolide Attenuates Myocardial Ischemia-Reperfusion Injury in Mice by Up-Regulating PPAR-α.

Andrographolide (AGP), a bioactive diterpene lactone, is an active constituent extracted from Andrographis paniculata. It has many biological activities, such as antioxidant, antitumor, antivirus, anti-inflammation, hepatoprotection, and cardioprotection. The aim of the present study is to investigate the cardioprotective effects of AGP in a mouse model of myocardial ischemia-reperfusion injury (MIRI). Adult male C57BL/6J mice were pre-treated orally with AGP (25mg/kg) for six days. After 30min of the left anterior descending coronary artery occlusion followed by 24h of reperfusion, mice received an additional dose of AGP. The results showed that: (i) AGP pretreatment significantly reduced myocardial infarct size and cardiac injury biomarkers in MIRI mice and improved left ventricular ejection fraction (EF) and fractional shortening (FS); (ii) AGP pretreatment attenuated MIRI-induced oxidative stress imbalance in MIRI mice by increasing total antioxidant capacity (T-AOC) and reducing the levels of hydrogen peroxide (H2O2), nitric oxide (NO), malondialdehyde (MDA), and dihydroethidium (DHE); (iii) AGP pretreatment increased Bcl-2 expression and decreased caspase-3 and Bax expression in ischemic myocardial tissue, along with a reduction in TUNEL-positive cells. Further analysis showed that stimulation by I/R decreased peroxisome proliferator-activated receptor-α (PPAR-α) expression in ischemic cardiac tissue, which was prevented by AGP administration. Moreover, administration of the PPAR-α antagonist GW6471 (1mg/kg) abolished the protective effect of AGP on oxidative stress and apoptosis in the ischemic heart tissue of mice stimulated by ischemia-reperfusion. Taken together, these results suggest that AGP attenuates MIRI-induced cardiac injury by up-regulating PPAR-α expression, thereby preventing oxidative stress and cellular apoptosis.

The physiological anti-hypertensive peptide catestatin and its common human variant Gly364Ser: differential cardiovascular effects in a rat model of hypertension.

Catestatin (CST), a 21-amino acids physiological peptide, has emerged as a key modulator of cardiovascular functions due to its anti-hypertensive and cardioprotective properties. However, the ramifications of the most common human variant of CST (viz. Gly364Ser) on cardiovascular pathophysiology remain partially understood. In this study, hypertension was induced in uninephrectomized rats by treatment with deoxycorticosterone-acetate and sodium chloride (DOCA-salt). The DOCA-salt-induced hypertensive (DSHR) animals were then intraperitoneally administered with either CST wild-type (CST-WT) or 364Ser variant (CST-Ser) peptide. CST-Ser was profoundly less effective than CST-WT in rescuing the elevated systolic blood pressure [from ~211 mmHg to ~176 mmHg, p<0.0001 (CST-Ser) versus ~116 mmHg, p<0.0001 (CST-WT)] and heart rate [from ~356 bpm to ~314 bpm, p=0.66 (CST-Ser) versus ~276 bpm, p=0.02 (CST-WT)]. CST-Ser also showed diminished effects in lowering diastolic blood pressure and mean arterial pressure in the DSHR animals. Furthermore, CST-Ser was inefficient/markedly less potent in rescuing the impaired contractile and diastolic function in DSHR animals [improvements in the contractility index by ~22 s-1 (CST-Ser), p=0.15 versus by ~84 s-1 (CST-WT), p<0.0001 and decrease in end-diastolic pressure by ~4 mmHg (CST-Ser), p=0.015 versus by ~14 mmHg (CST-WT), p<0.0001]. Moreover, CST-Ser exerted less potent anti-inflammatory effects on the DSHR hearts than CST-WT. These findings are in concordance with the elevated systolic/diastolic blood pressure observed in Ser variant carriers from various human populations. This study provides compelling evidence for the diminished anti-hypertensive and cardioprotective effects of the CST-Gly364Ser variant.