Cardiac Hypertrophy In Rats Research Articles

Effect and mechanism of leonurine on pressure overload-induced cardiac hypertrophy in rats

To investigate the effects of leonurine(Leo) on abdominal aortic constriction(AAC)-induced cardiac hypertrophy in rats and its mechanism. A rat model of pressure overload-induced cardiac hypertrophy was established by AAC method. After 27-d intervention with high-dose(30 mg·kg~(-1)) and low-dose(15 mg·kg~(-1)) Leo or positive control drug losartan(5 mg·kg~(-1)), the cardiac function was evaluated by hemodynamic method, followed by the recording of left ventricular systolic pressure(LVSP), left ventricular end-diastolic pressure(LVESP), as well as the maximum rate of increase and decrease in left ventricular pressure(±dp/dt_(max)). The degree of left ventricular hypertrophy was assessed based on heart weight index(HWI) and left ventricular mass index(LVWI). Myocardial tissue changes and the myocardial cell diameter(MD) were measured after hematoxylin-eosin(HE) staining. The contents of angiotensin Ⅱ(AngⅡ) and angiotensin Ⅱ type 1 receptor(AT1 R) in myocardial tissue were detected by ELISA. The level of Ca~(2+) in myocardial tissue was determined by colorimetry. The protein expression levels of phospholipase C(PLC), inositol triphosphate(IP3), AngⅡ, and AT1 R were assayed by Western blot. Real-time quantitative PCR(qRT-PCR) was employed to determine the mRNA expression levels of β-myosin heavy chain(β-MHC), atrial natriuretic factor(ANF), AngⅡ, and AT1 R. Compared with the model group, Leo decreased the LVSP, LVEDP, HWI, LVWI and MD values, but increased ±dp/dt_(max) of the left ventricle. Meanwhile, it improved the pathological morphology of myocardial tissue, reduced cardiac hypertrophy, edema, and inflammatory cell infiltration, decreased the protein expression levels of PLC, IP3, AngⅡ, AT1 R, as well as the mRNA expression levels of β-MHC, ANF, AngⅡ, AT1 R, c-fos, and c-Myc in myocardial tissue. Leo inhibited AAC-induced cardiac hypertrophy possibly by influencing the RAS system.

EFFECT OF AEROBIC AND ANAEROBIC TRAINING ON DIFFERENT ERGOMETERS IN RAT MUSCLE AND HEART TISSUES.

Analyze the effects of aerobic and anaerobic training on different ergometers on muscle and cardiac hypertrophy in rats. The animals were separated into the following groups: Control (C), Aerobic Training in Water (ATW), Resistance Training in Water (RTW), Aerobic Training on Treadmill (ATT), and Resistance Training in Climbing (RTC). All training protocols were carried out for 4 weeks, 3 times/week. The cross-sectional area (CSA) of the gastrocnemius muscle cells and the areas of the cardiomyocytes were measured. In the fast-twitch fibers, there was an increase in CSA in the RTW and RTC groups compared to the ATW (p<0.01 and p<0.01) and ATT groups (p<0.01 and p<0.01). In the slow-twitch fibers, the ATW and ATT groups demonstrated a lower CSA compared to the RTW (p=0.03 and p<0.00) and RTC groups (p<0.01 and p<0.01). In the cardiomyocytes, there was an increase in the area of the RTW and RTC groups compared to groups C (p<0.01; p<0.01), ATW (p=0.02; p<0.01), and ATT (p<0.01; p<0.01). The anaerobic training effectively promotes hypertrophy in the fast-twitch fibers and the cardiomyocytes. Level of Evidence V; Animal experimental study .

Azilsartan ameliorates ventricular hypertrophy in rats suffering from pressure overload-induced cardiac hypertrophy by activating the Keap1-Nrf2 signalling pathway.

Investigate if azilsartan protects against myocardial hypertrophy by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated pathways. Abdominal aortic constriction (AAC)-induced cardiac hypertrophy in rats was applied. Azilsartan or vehicle was administered daily for 6 weeks in sham or AAC rats. Cardiac morphology and ventricular function were determined. Azilsartan effects upon neonatal rat cardiomyocyte (NRCM) hypertrophy and molecular mechanisms were studied in angiotensin (Ang) II-stimulated NRCMs in vitro. Nrf2-small interfering RNA (siRNA) was used to knockdown Nrf2 expression. Messenger RNA (mRNA)/protein expression of Kelch-like erythroid cell-derived protein (Keap)1 and Nrf2 and its downstream antioxidant enzymes was determined by real-time reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. Azilsartan treatment ameliorated cardiac hypertrophy/fibrosis significantly in AAC rats. Azilsartan increased expression of Nrf2 protein but decreased expression of Keap1 protein. Upregulation of protein expression of Nrf2's downstream antioxidant enzymes by azilsartan treatment was observed. Azilsartan inhibited Ang II-induced NRCM hypertrophy significantly and similar effects on the Keap1-Nrf2 pathway were observed in vivo. Nrf2 knockdown markedly counteracted the beneficial effects of azilsartan on NRCM hypertrophy and the Keap1-Nrf2 pathway. Azilsartan restrained pressure overload-induced cardiac remodelling by activating the Keap1-Nrf2 pathway and increasing expression of downstream antioxidant enzymes to alleviate oxidative stress.

Aloin alleviates pathological cardiac hypertrophy via modulation of the oxidative and fibrotic response

AimsPathological cardiac hypertrophy is a characteristic feature in many cardiovascular diseases (CVDs). Aloin is an anthraquinone glycoside from Aloe species, and the effect of aloin on cardiac hypertrophy and associated fibrotic changes have not been elucidated. This study investigated the effect of aloin against the isoproterenol (ISO)-induced cardiac hypertrophy in rats. Main methodsCardiac hypertrophy experimental model was induced in rats by subcutaneous injection of ISO for 14 days. Meanwhile, the animals were administered orally with aloin at doses of 25 and 50 mg/kg/day. On the 15th day, cardiac echocardiography was performed, the heart was collected and subjected for histopathological, gene expression, and immunoblot studies. Additionally, the effect of aloin on ISO-induced hypertrophic changes in H9c2 cells was investigated. Key findingsAloin markedly alleviated ISO-induced heart injury, reduced cardiac hypertrophy, improved cardiac function, and histological alterations in the heart. Mechanistically, aloin attenuated ISO-induced fibrosis via inhibition of the levels of collagen I, α-smooth muscle actin (α-SMA), fibronectin, transforming growth factor-β (TGF-β) and pSmad2/3 proteins in the heart. Aloin alleviated ISO-induced myocardial oxidative damage and up-regulated the levels of antioxidant transcription factor nuclear factor erythroid 2–related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) proteins. Moreover, aloin treatment attenuated ISO-induced hypertrophic changes and the generation of reactive oxygen species (ROS) in H9c2 cells in vitro. SignificanceOur findings demonstrated that aloin alleviated ISO-induced cardiac hypertrophy and fibrosis via inhibiting TGF-β/pSmad2/3 signaling and restoring myocardial antioxidants, and therefore has promising therapeutic potential against cardiac hypertrophy and fibrosis.

YQFM alleviated cardiac hypertrophy by apoptosis inhibition and autophagy regulation via PI3K/AKT/mTOR pathway

Ethnopharmacological relevanceAs a traditional compound preparation of Chinese medicine, Yiqi Fumai lyophilized injection (YQFM) has protective effects on various cardiac diseases including cardiac hypertrophy, which is the primary cause of arrhythmia. However, the involved mechanism remains unclear. Aim of the study: This study was projected to investigate whether YQFM could prevent cardiac hypertrophy and arrhythmia concurrence. Materials and Methods: The cardiac hypertrophy rats were established by transverse aortic ligation and the H9c2 hypertrophy cardiomyocyte was induced by angiotensin II (AngII). The electrocardiogram (ECG) was conducted to estimate the arrhythmia occurrence of cardiac hypertrophy rats under isoprenaline (iso) treatment. The cardiac related indicators and histopathology were also detected. The protective effects of YQFM on H9c2 hypertrophy cardiomyocyte were determined by the cell size measurement, apoptosis detection and mitochondrial membrane potential measurement. The cardiac hypertrophy relative proteins (ANP and BNP), autophagy related factors (LC3II, p62 and Beclin-1), apoptosis related markers (p53, caspase 3, Bax and Bcl-2) and the PI3K/AKT/mTOR pathway expressions were all measured by Western blot. Results: YQFM decreased the arrhythmia occurrence and improved cardiac function in cardiac hypertrophy rats. YQFM also reduced the H9c2 cardiomyocyte size and alleviated the cardiomyocyte apoptosis induced by AngII. In addition, YQFM inhibited cell apoptosis by increasing Bcl-2/Bax ratio and decreasing caspase 3 and p53 expressions in vitro and vivo. Meanwhile, YQFM regulated the autophagy pathway by down-regulating of LC3II and Beclin-1 expressions, as well as up-regulating of p62 expression. Finally, the results showed that YQFM could activate the PI3K/AKT/mTOR pathway by enhancing the p-AKT, p-PI3K and p-mTOR expressions. Conclusion: Our results displayed that YQFM attenuated the cardiac hypertrophy by apoptosis inhibition and autophagy regulation via PI3K/AKT/mTOR pathway.

Neutrophil-like cell membrane-coated siRNA of lncRNA AABR07017145.1 therapy for cardiac hypertrophy via inhibiting ferroptosis of CMECs

Cardiac microvascular dysfunction is associated with cardiac hypertrophy and can eventually lead to heart failure. Dysregulation of long non-coding RNAs (lncRNAs) has recently been recognized as one of the key mechanisms involved in cardiac hypertrophy. However, the potential roles and underlying mechanisms of lncRNAs in cardiac microvascular dysfunction have not been explicitly delineated. Our results confirmed that cardiac microvascular dysfunction was related to cardiac hypertrophy and ferroptosis of cardiac microvascular endothelial cells (CMECs) occurred during cardiac hypertrophy. Using a combination of in vivo and in vitro studies, we identified a lncRNA AABR07017145.1, named as lncRNA AAB for short, and revealed that lncRNA AAB was upregulated in the hearts of cardiac hypertrophy rats as well as in the Ang II-induced CMECs. Importantly, we found that lncRNA AAB sponged and sequestered miR-30b-5p to induce the imbalance of MMP9/TIMP1, which enhanced the activation of transferrin receptor 1 (TFR-1) and then eventually led to the ferroptosis of CMECs. Moreover, we have developed a delivery system based on neutrophil membrane (NM)-camouflaged mesoporous silica nanocomplex (MSN) for inhibition of cardiac hypertrophy, indicating the potential role of silenced lncRNA AAB (si-AAB) and overexpressed miR-30b-5p as the novel therapy for cardiac hypertrophy.

MiR-100-5p regulates cardiac hypertrophy through activation of autophagy by targeting mTOR.

Autophagy has been proved to play a vital role in cardiac hypertrophy. The present study was designed to investigate the relationship between miR-100-5p and autophagy in the development of cardiac hypertrophy. Here, miR-100-5p expression was detected in abdominal aortic coarctation (AAC)-induced cardiac hypertrophy rats and AngiotensinII (Ang II)-stimulated cardiomyocytes. In vitro and in vivo experiments were performed to explore the function of miR-100-5p on autophagy and cardiac hypertrophy. We also investigated the mechanism of miR-100-5p on autophagy with dual-luciferase reporter assays, RNA immunoprecipitation (RIP), quantitative real-time PCR (qRT-PCR), western blot, immunofluorescence, and transmission electron microscopy (TEM). The results showed that miR-100-5p was highly expressed in hypertrophic hearts and Ang II-induced cardiomyocytes. Overexpression of miR-100-5p promoted the expression of cardiac hypertrophy markers ANP, BNP and β-MHC and cell surface area, while those were suppressed by miR-100-5p inhibitor. Knockdown of miR-100-5p by antagomiR significantly improves cardiac function and attenuate cardiac hypertrophy in vivo. Mechanistic investigation has found that miR-100-5p promote autophagy by targeting mTOR. Inhibition of autophagy by 3-methyladenine (3-MA) or mTOR overexpression could reverse the function of miR-100-5p in cardiac hypertrophy. These results elucidate that miR-100-5p promoted the pathogenesis of cardiac hypertrophy through autophagy activation by targeting mTOR.

Pharmacokinetics/pharmacometabolomics-pharmacodynamics reveals the synergistic mechanism of a multicomponent herbal formula, Baoyuan decoction against cardiac hypertrophy

Multicomponent herbal formulas (MCHFs) have earned a wide reputation for their definite efficacy in preventing or treating chronic complex diseases. However, holistic elucidation of the causal relationship between the bioavailable ingredients of MCHFs and their multitarget interactions is very challenging. To solve this problem, pharmacokinetics/pharmacometabolomics-pharmacodynamics (PK/PM-PD) combined with a multivariate biological correlation-network strategy was developed and applied to a classic MCHF, Baoyuan decoction (BYD), to clarify its active components and synergistic mechanism against cardiac hypertrophy (CH). First, multiple plasma metabolic biomarkers for β-adrenergic agonist-induced CH rats were identified by using untargeted metabolomic profiling, and then, these CH-associated endogenous metabolites and the absorbed BYD-compounds in plasma at different treatment stages after oral administration of BYD were analyzed by using targeted PK and PM. Second, the dynamic relationship of BYD-related compounds and CH-associated endogenous metabolites and signaling pathways was built by using multivariate and bioinformatic correlation analysis. Finally, metabolic-related PD indicators were predicted and further verified by biological tests. The results demonstrated that the bioavailable BYD-compounds, such as saponins and flavonoids, presented differentiated and distinctive metabolic features and showed positive or negative correlations with various CH-altered metabolites and PD-indicators related to gut microbiota metabolism, amino acid metabolism, lipid metabolism, energy homeostasis, and oxidative stress at different treatment stages. This study provides a novel strategy for investigating the dynamic interaction between BYD and the biosystem, providing unique insight for disclosing the active components and synergistic mechanisms of BYD against CH, which also supplies a reference for other MCHF related research.

Molecular Mechanisms of Nigella sativa- and Nigella sativa Exercise-Induced Cardiac Hypertrophy in Rats.

Background In our lab, we demonstrated cardiac hypertrophy induced by long-term administration of Nigella sativa (Ns) with enhanced function. Therefore, we aim to investigate the molecular mechanisms of Ns-induced cardiac hypertrophy, compare it with that induced by exercise training, and explore any possible synergistic effect of these two interventions. Method Twenty adult Wistar male rats were divided into control (C), Ns-fed (N.s.), exercise-trained (Ex.), Ns-fed exercise-trained (N.s.Ex.) groups. 800 mg/kg of Ns was administered orally to N.s. rats. Ex. rats were trained on a treadmill with speed 18 m/min and grade 32° for two hours daily, and the N.s.Ex. group underwent both interventions. After 8 weeks, Immunohistochemical slides of the left ventricles were prepared using rat growth hormone (GH), insulin-like growth factor I (IGF-I), angiotensin-II receptors 1 (AT-I), endothelin-I (ET-1), Akt-1, and Erk-1. Cell diameter and number of nuclei were measured. Results Cardiomyocyte diameter, number of nuclei, GH, and Akt were significantly higher in N.s, Ex., and N.s.Ex groups compared with the controls. IGF-I, AT-1, and ET-1 were significantly higher in Ex. rats only compared with the controls. Erk-1 was lower in N.s., Ex., and N.s.Ex. compared with the controls. Conclusion We can conclude that Ns-induced cardiac hypertrophy is mediated by the GH-IGF I-PI3P-Akt pathway. Supplementation of Ns to exercise training protocol can block the upregulation of AT-I and ET-1. The combined N.s. exercise-induced cardiac hypertrophy might be a superior model of physiological cardiac hypertrophy and be used as a prophylactic therapy for athletes who are engaged in vigorous exercise activity.

Ambient air PM2.5 exposure induces heart injury and cardiac hypertrophy in rats through regulation of miR-208a/b, α/β-MHC, and GATA4

Ambient air fine particulate matter (PM2.5) may increase cardiovascular disease risks. In this study, we investigated the miR-208/GATA4/myosin heavy chain (MHC) regulation mechanisms on cardiac injury in rats after PM2.5 exposure via an animal inhalation device. The results showed that PM2.5 exposure for 2 months caused pathological heart injury, reduced nucleus-cytoplasm ratio, and increased the levels of CK-MB and cTnI, showing cardiac hypertrophy. Oxidative stress and inflammatory responses were also observed in rats’ hearts exposed to PM2.5. Of note, PM2.5 exposure for 2-month significantly elevated GATA4 and β-MHC mRNA and protein expression compared with the corresponding controls, along with the high-expression of miR-208b. The ratios of β-MHC/α-MHC expression induced by PM2.5 were remarkably raised in comparison to their controls. It suggested that the up-regulation of miR-208b/β-MHC and GATA4 and the conversion from α-MHC to β-MHC may be the important causes of cardiac hypertrophy in rats incurred by PM2.5.

Zonisamide alleviates cardiac hypertrophy in rats by increasing Hrd1 expression and inhibiting endoplasmic reticulum stress.

Antiepileptic drug zonisamide has been shown to be curative for Parkinson's disease (PD) through increasing HMG-CoA reductase degradation protein 1 (Hrd1) level and mitigating endoplasmic reticulum (ER) stress. Hrd1 is an ER-transmembrane E3 ubiquitin ligase, which is involved in cardiac dysfunction and cardiac hypertrophy in a mouse model of pressure overload. In this study, we investigated whether zonisamide alleviated cardiac hypertrophy in rats by increasing Hrd1 expression and inhibiting ER stress. The beneficial effects of zonisamide were assessed in two experimental models of cardiac hypertrophy: in rats subjected to abdominal aorta constriction (AAC) and treated with zonisamide (14, 28, 56 mg · kg-1 · d-1, i.g.) for 6 weeks as well as in neonatal rat cardiomyocytes (NRCMs) co-treated with Ang II (10 μM) and zonisamide (0.3 μM). Echocardiography analysis revealed that zonsiamide treatment significantly improved cardiac function in AAC rats. We found that zonsiamide treatment significantly attenuated cardiac hypertrophy and fibrosis, and suppressed apoptosis and ER stress in the hearts of AAC rats and in Ang II-treated NRCMs. Importantly, zonisamide markedly increased the expression of Hrd1 in the hearts of AAC rats and in Ang II-treated NRCMs. Furthermore, we demonstrated that zonisamide accelerated ER-associated protein degradation (ERAD) in Ang II-treated NRCMs; knockdown of Hrd1 abrogated the inhibitory effects of zonisamide on ER stress and cardiac hypertrophy. Taken together, ourresults demonstrate that zonisamide is effective in preserving heart structure and function in the experimental models of pathological cardiac hypertrophy. Zonisamide increases Hrd1 expression, thus preventing cardiac hypertrophy and improving the cardiac function of AAC rats.

Rutaecarpine Ameliorates Pressure Overload Cardiac Hypertrophy by Suppression of Calcineurin and Angiotensin II

Cardiac hypertrophy is a major pathological process to result in heart failure and sudden death. Rutaecarpine, a pentacyclic indolopyridoquinazolinone alkaloid extracted from Evodia rutaecarpa with multiple pharmacological activities, yet the underlying protective effects and the mechanisms on cardiac hypertrophy remain unclear. This study aimed to evaluate the potential effects of rutaecarpine on pressure overload cardiac hypertrophy. Cardiac hypertrophy in rat was developed by abdominal aortic constriction (AAC) for 4 weeks, which was improved by rutaecarpine supplementation (20 or 40 mg/kg/day, i.g.) for another 4 weeks. The level of angiotensin II was increased; the mRNA expression and the activity of calcineurin in the left ventricular tissue were augmented following cardiac hypertrophy. Rutaecarpine administration decreased angiotensin II content and reduced calcineurin expression and activity. Noteworthily, in angiotensin II-induced cardiomyocytes, rutaecarpine ameliorated the hypertrophic effects in a dose-dependent manner and downregulated the increased mRNA expression and activity of calcineurin. In conclusion, rutaecarpine can improve cardiac hypertrophy in pressure overload rats, which may be related to the inhibition of angiotensin II-calcineurin signal pathway.

Effect of isoproterenol and thyroxine in herbal drug used as cardiac hypertrophy

The impact of A. calamus extract and C. Pereira extract on heart hypertrophy caused by isoproterenol. A. calamus extract & C. Pereira extract on heart hypertrophy by thyroxine. MATERIAL AND METHOD a. Animal House Pharmacy School (Wistar rats), measuring 180-250 grammes, BIT Meerut (UP). One week before the research began, they were kept separately in polypropylene cages in a quarantine room. b. C. Pareira and A. calamus rhizomes from the School of Pharmacy at the Medicinal Garden, BIT, Merrut, UP, India. METHODS  Influence of C. Pareria Extract on Isoproterenol- induced cardiac hypertrophy in rats.  Influence of A. Calamus Extract on Isoproterenol- induced cardiac hypertrophy in rats. Influence of C. Pareria Extract on Thyroxine- induced cardiac hypertrophy in rats  Influence of A Calamus Extract on Thyroxine- induced cardiac hypertrophy in rats. RESULTS In comparison with control and C. Pareira and A. Calamus as well as amlodipine treated groups in the ISO treatment community, no major alteration was identified in the MAP. There was no MAP change in T4 compared with controls and groups C. pareira and amlodipine treated with T4. Significantly increased T4 (P < O.O1) HR administration against power.No significant change in HR was detected in C. Pareira and A. calamus. CONCULSION Cissampelos pareira and Acorn calamus effect in cardiac hypertrophy induced by isoproterenol Isoproterenol chronic administration (5 mg/lcg/day, 30 days), cardiac hypertrophy, cardiac weight ratio, angiotensin II, tumour factor necrosis, calcineurin, oxide/reactive nitrients, NaV K'^-ATPase, antioxidant and NaVK'^-ATPase, active component antioxidants Both of these changes in the therapy of Cissampelos pareira (100 and 200 mg/kg/day, 30 days) and Acorus calamus (100 and 200 mg/kg/day, 30 days) were substantially enhanced. Effect of thyroxin-induced cardiac hypertrophy on Cissampelos pareira and Acorus calamus The continuous thyroxine (0.1 mg/kg/day, for 30 days) was characterised by hypertropy of the heart and heart and body weight ratios, Angiotensin II, tumour necrosis factor, calcineurine, nitric oxide and thyrobarbituric acid, and a substantial decrease. Hypertrophy of the heart Cissampelos pareira (100 and 200 mg/kg/day) and Acorus calamus (100 and 200 mG/kg/day) have been decreased to almost normal in the next 30 days.

Identification of serum predictors of n-acetyl-l-cysteine and isoproterenol induced remodelling in cardiac hypertrophy.

Cardiac hypertrophy (CH), leading to cardiac failure is due to chronic metabolic alterations occurring during cellular stress. Besides the already known relationship between oxidative stress and CH, there are implications of reductive stress leading to CH. This study attempted to develop reductive stress-based CH rat model using n-acetyl-L-cysteine (NAC), a glutathione agonist that was compared with typical isoproterenol (ISO) induced CH model. The main objective was to identify serum metabolites that can serve as potent predictors for seven routine clinical and diagnostic parameters in CH: 3-hydroxybutyrate (3-HB), lactic acid (LA), urea, and ECG-CH parameters (QRS complex, R-amplitude, R-R interval, heart rate) that were hypothesized to underlie metabolic remodelling in this study. CH was assessed using electrocardiography, hypertrophic index and histopathological analysis (H&E stain) in both ventricles after 2 weeks. Gas chromatography mass spectroscopy analysis (GC-MS) identified unique metabolite finger-prints. Correlation and pattern analysis revealed strong relationships between specific metabolites and parameters (Pearson’s score > 0.7) of this study. Multiple regression analysis (MRA) for the strongly related metabolites (independent variables) with each of the seven parameters (dependent variables) identified significant predictors for the latter namely fructose, valine, butanoic acid in NAC and cholesterol, erythrose, isoleucine in ISO models, with proline and succinic acid as common for both models. Metabolite set enrichment analysis (MSEA) of those significant predictors (p < 0.05) mapped butyrate metabolism as highly influential pathway in NAC, with arginine-proline metabolism and branched chain amino acid (BCAA) degradation as common pathways in both models, thus providing new insights towards initial metabolic remodeling in the pathogenesis of CH.

The protective effect of isosteviol sodium on cardiac function and myocardial remodelling in transverse aortic constriction rat.

Pathological hypertrophy contributes to heart failure and there is not quite effective treatment to invert this process. Isosteviol has been shown to protect the heart against ischaemia‐reperfusion injury and isoproterenol‐induced cardiac hypertrophy, but its effect on pressure overload‐induced cardiac hypertrophy is still unknown. Pressure overload induced by transverse aortic constriction (TAC) causes cardiac hypertrophy in rats to mimic the pathological condition in human. This study examined the effects of isosteviol sodium (STVNa) on cardiac hypertrophy by the TAC model and cellular assays in vitro. Cardiac function test, electrocardiogram analysis and histological analysis were conducted. The effects of STVNa on calcium transient of the adult rat ventricular cells and the proliferation of neonatal rat cardiac fibroblasts were also studied in vitro. Cardiac hypertrophy was observed after 3‐week TAC while the extensive cardiac dysfunction and electronic remodelling were observed after 9‐week TAC. Both STVNa and sildenafil (positive drug) treatment reversed the two process, but STVNa appeared to be more superior in some aspects and did not change calcium transient considerably. STVNa also reversed TAC‐induced cardiac fibrosis in vivo and TGF‐β1‐induced fibroblast proliferation in vitro. Moreover, STVNa, but not sildenafil, reversed impairment of the autonomic nervous system induced by 9‐week TAC.

Selective changes in cytosolic β-adrenergic cAMP signals and L-type Calcium Channel regulation by Phosphodiesterases during cardiac hypertrophy

Background In cardiomyocytes, phosphodiesterases (PDEs) type 3 and 4 are the predominant enzymes that degrade cAMP generated by β-adrenergic receptors (β-ARs), impacting notably the regulation of the L-type Ca2+ current (ICa,L). Cardiac hypertrophy (CH) is accompanied by a reduction in PDE3 and PDE4, however, whether this affects the dynamic regulation of cytosolic cAMP and ICa,L is not known.Methods and Results CH was induced in rats by thoracic aortic banding over a time period of five weeks and was confirmed by anatomical measurements. Left ventricular myocytes (LVMs) were isolated from CH and sham-operated (SHAM) rats and transduced with an adenovirus encoding a Förster resonance energy transfer (FRET)-based cAMP biosensor or subjected to the whole-cell configuration of the patch-clamp technique to measure ICa,L. Aortic stenosis resulted in a 46% increase in heart weight to body weight ratio in CH compared to SHAM. In SHAM and CH LVMs, a short isoprenaline stimulation (Iso, 100 nM, 15 s) elicited a similar transient increase in cAMP with a half decay time (t1/2off) of ~50 s. In both groups, PDE4 inhibition with Ro 20-1724 (10 μM) markedly potentiated the amplitude and slowed the decline of the cAMP transient, this latter effect being more pronounced in SHAM (t1/2off ~ 250 s) than in CH (t1/2off ~ 150 s, P < 0.01). In contrast, PDE3 inhibition with cilostamide (1 μM) had no effect on the amplitude of the cAMP transient and a minimal effect on its recovery in SHAM, whereas it potentiated the amplitude and slowed the decay in CH (t1/2off ~ 80 s). Iso pulse stimulation also elicited a similar transient increase in ICa,L in SHAM and CH, although the duration of the rising phase was delayed in CH. Inhibition of PDE3 or PDE4 potentiated ICa,L amplitude in SHAM but not in CH. Besides, while only PDE4 inhibition slowed down the decline of ICa,L in SHAM, both PDE3 and PDE4 contributed in CH.Conclusion These results identify selective alterations in cytosolic cAMP and ICa,L regulation by PDE3 and PDE4 in CH, and show that the balance between PDE3 and PDE4 for the regulation of β-AR responses is shifted toward PDE3 during CH.

Myocardial hypertrophy is prevented by farnesol through oxidative stress and ERK1/2 signaling pathways

Farnesol is a sesquiterpene found in several plants, with multiple pharmacological activities. However, pharmacological actions of farnesol in the treatment of cardiac hypertrophy are not yet reported. This study aimed to investigate the effect and regulatory mechanisms of farnesol against isoproterenol-induced pathological cardiac hypertrophy. Male Wistar rats were treated for 8 days with isoproterenol (4.5 mg/kg; i. p.) and with farnesol (50 μM; i. p.). Hearts were subjected to evaluation of left ventricular developed pressure (LVDP), coronary pressure, electrocardiogram, histopathological analysis, reactive oxygen species (ROS) generation, antioxidant enzyme activity, and pro- and anti-apoptosis protein expression. The results showed that severe impairment of LVDP induced by cardiac hypertrophy was significantly prevented by farnesol treatment. Moreover, farnesol attenuated electrocardiographic changes that are characteristic of cardiac hypertrophy, as well as prevented the increase of fibrosis and migration of inflammatory cells in cardiac tissue. Additionally, farnesol treatment prevented the increase of cardiac ROS generation and restored the activity of endogenous antioxidant enzymes, such as SOD and catalase. It was also evidenced that farnesol decreased the ERK1/2, Bax and Caspase 3 activation, and an increase of AKT and Bcl-2 protein expression, which can be associated with the pathological cardiac remodeling and also with cardioprotection mediated by farnesol, respectively. These results suggest that farnesol is a novel therapeutic agent for amelioration of cardiac hypertrophy in rats.

The cardiac protection of Baoyuan decoction via gut-heart axis metabolic pathway

BackgroundGut-heart axis has emerged as a novel concept to provide new insights into the complex mechanisms of heart failure (HF) and offer new therapeutic targets. Cardiac hypertrophy (CH) is one of the etiological agents contributing to the development of HF. Baoyuan Decoction (BYD), a traditional Chinese medicine (TCM) formula, exhibits unambiguous effects on treating CH and preventing HF. Previously, we have reported that BYD-targeted endogenous metabolites are potentially linked to gut microbiota metabolism, but the contribution of gut microbiota and metabolic interaction to the cardioprotective efficacy of BYD remains to be elucidated. PurposeTo investigate whether the gut microbiota plays a key role in anti-CH effects of BYD. Study designA comprehensive strategy via incorporating pharmacodynamics, microbiomics, metabolomics, and microflora suppression model was adopted to investigate the links between the microbiota–host metabolic interaction and BYD efficacy in CH rats. MethodFirstly, the efficacy evaluation of BYD in treating chronic isoproterenol (ISO)-induced CH rats was performed by using multiple pharmacodynamic approaches. Then, the fecal metabolomics and 16S rRNA sequencing techniques were used to obtain the microbial and metabolic features of BYD against CH. After that, the potential gut-heart axis-based mechanism of BYD against CH was predicted by bioinformatic network analysis and validated by multiple molecular biology approaches. Finally, the antibiotics (AB)-induced gut microbiota suppression was employed to investigate whether the anti-CH effects of BYD is associated with the gut microflora. ResultsThe fecal microbial communities and metabolic compositions were significantly altered in ISO-induced CH rats, while BYD effectively ameliorated the CH-associated gut microbiota dysbiosis, especially of Firmicutes and Bacteroidetes, and time-dependently alleviated the disturbance of fecal metabolome and reversed the changes of key CH and gut microbiota-related metabolites, such as short/medium chain fatty acids, primary/secondary bile acids, and amino acids. The mechanism study showed that the anti-CH effect of BYD was related to inhibition of the derivatives of arginine and tryptophan and their downstream pro-hypertrophic, pro-inflammatory, and pro-oxidant signaling pathways. The following microflora suppression test showed that BYD-mediated myocardial protection was decreased either in pharmacodynamics or in metabolic modulation. ConclusionThis study demonstrates that the protection of BYD against CH is partially gut microbiota dependent, and the regulatory effects of gut metabolism-related tryptophan and arginine derivatives is an important cardioprotection mechanism of BYD.

Extracellular cyclophilin A induces cardiac hypertrophy via the ERK/p47phox pathway

Excessive reactive oxygen species (ROS) are a critical driver of cardiac hypertrophy developing into heart failure. Cyclophilin A (CyPA), a member of the cyclophilin family, has been highlighted as a main secreted ROS-induced factor. The mechanism by which extracellular CyPA interacts with cardiomyocytes is unclear. We showed that extracellular CyPA is upregulated in cardiac hypertrophy rats and expressed around hypertrophic cardiomyocytes. Cell experiments further confirmed that extracellular CyPA induces H9c2 cardiomyocytes hypertrophy via ROS generation. Extracellular CyPA-induced ROS is derived from nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase, and extracellular CyPA activates p47phox membrane translocation through ERK1/2 pathway. When blocking extracellular matrix metalloproteinase inducer (EMMPRIN), most of the extracellular CyPA effects were significantly inhibited. The current study shows that extracellular CyPA is one of the key factors linking oxidative stress and cardiac hypertrophy, and may be a potential target for cardiac hypertrophy therapy.

Sustained increased CaMKII phosphorylation is involved in the impaired regression of isoproterenol-induced cardiac hypertrophy in rats

To understand the mechanism underlying the regression of cardiac hypertrophy, we investigated the pathological changes after isoproterenol (ISO) withdrawal in ISO-induced cardiomyopathy models in rats and neonatal cardiomyocytes. Cardiac hypertrophy was induced in rats by two weeks of ISO administration; however, the hypertrophy did not regress after three weeks of natural maintenance after ISO administration was withdrawn (ISO-wdr group). The remaining hypertrophy in the ISO-wdr group was accompanied by a sustained increase in the level of phosphorylated Ca2+/calmodulin-dependent protein kinase II (p-CaMKII). Additionally, the increased expression levels of histone deacetylase 4 (HDAC4) and the CaV1.2 channel and amounts of CaMKII bound with HDAC4 and CaV1.2 were not recovered in the ISO-wdr group. The results in cardiomyocyte models were similar to those seen in rat models. Losartan, metoprolol or amlodipine neither ameliorated the increase in atrial natriuretic peptide nor inhibited the increase in p-CaMKII and bound CaMKII. In contrast, autocamtide-2-related inhibitor peptide, a CaMKII inhibitor, reduced these increases. This study investigated the phosphorylation status of CaMKII after hypertrophic stimulus was withdrawn for the first time and proposed that CaMKII as well as its complexes with CaV1.2 could be potential targets to achieve effective regression of cardiac hypertrophy.