SNX5-Rab11a protects against cardiac hypertrophy through regulating LRP6 membrane translocation.

BACKGROUNDS: Pathological cardiac hypertrophy is considered one of the independent risk factors for heart failure, with a rather complex pathogenic machinery. Sorting nexins (SNXs), denoting a diverse family of cytoplasmic- and membrane-associated phosphoinositide-binding proteins, act as a pharmacological target against specific cardiovascular diseases including heart failure. Family member SNX5 was reported to play a pivotal role in a variety of biological processes. However, contribution of SNX5 to the development of cardiac hypertrophy, remains unclear. METHODS: Mice underwent transverse aortic constriction (TAC) to induce cardiac hypertrophy and simulate pathological conditions. TAC model was validated using echocardiography and histological staining. Expression of SNX5 was assessed by western blotting. Then, SNX5 was delivered through intravenous administration of an adeno-associated virus serotype 9 carrying cTnT promoter (AAV9-cTnT-SNX5) to achieve SNX5 cardiac-specific overexpression. To assess the impact of SNX5, morphological analysis, echocardiography, histological staining, hypertrophic biomarkers, and cardiomyocyte contraction were evaluated. To unravel potential molecular events associated with SNX5, interactome analysis, fluorescence co-localization, and membrane protein profile were evaluated. RESULTS: Our results revealed significant downregulated protein level of SNX5 in TAC-induced hypertrophic hearts in mice. Interestingly, cardiac-specific overexpression of SNX5 improved cardiac function, with enhanced left ventricular ejection fraction, fraction shortening, as well as reduced cardiac fibrosis. Mechanistically, SNX5 directly bound to Rab11a, increasing membrane accumulation of Rab11a (a Rab GTPase). Afterwards, this intricate molecular interaction upregulated the membrane content of low-density lipoprotein receptor-related protein 6 (LRP6), a key regulator against cardiac hypertrophy. Our comprehensive assessment of siRab11a expression in HL-1 cells revealed its role in antagonism of LRP6 membrane accumulation under SNX5 overexpression. CONCLUSIONS: This study revealed that binding of SNX5 with LRP6 triggers their membrane translocation through Rab11a assisting, defending against cardiac remodeling and cardiac dysfunction under pressure overload. These findings provide new insights into the previously unrecognized role of SNX5 in the progression of cardiac hypertrophy.

Effects of sacubitril-valsartan on aging-related cardiac dysfunction.

Heart failure (HF) remains a huge medical burden worldwide, with aging representing a major risk factor. Here, we report the effects of sacubitril/valsartan, an approved drug for HF with reduced EF, in an experimental model of aging-related HF with preserved ejection fraction (HFpEF). Eighteen-month-old female Fisher 344 rats were treated for 12 weeks with sacubitril/valsartan (60 mg/kg/day) or with valsartan (30 mg/kg/day). Three-month-old rats were used as control. No differential action of sacubitril/valsartan versus valsartan alone, either positive or negative, was observed. The positive effects of both sacubitril/valsartan and valsartan on cardiac hypertrophy was evidenced by a significant reduction of wall thickness and myocyte cross-sectional area. Contrarily, myocardial fibrosis in aging heart was not reduced by any treatment. Doppler echocardiography and left ventricular catheterization evidenced diastolic dysfunction in untreated and treated old rats. In aging rats, both classical and non-classical renin-angiotensin-aldosterone system (RAAS) were modulated. In particular, with respect to untreated animals, both sacubitril/valsartan and valsartan showed a partial restoration of cardioprotective non-classical RAAS. In conclusion, this study evidenced the favorable effects, by both treatments, on age-related cardiac hypertrophy. The attenuation of cardiomyocyte size and hypertrophic response may be linked to a shift towards cardioprotective RAAS signaling. However, diastolic dysfunction and cardiac fibrosis persisted despite of treatment and were accompanied by myocardial inflammation, endothelial activation, and oxidative stress.

Carnosol suppresses cardiomyocyte hypertrophy via promoting the activation of AMPK pathway.

Pathological cardiac hypertrophy is associated with adverse cardiovascular events and can gradually lead to heart failure, arrhythmia, and even sudden death. However, the current development of treatment strategies has been unsatisfactory. Therefore, it is of great significance to find new and effective drugs for the treatment of myocardial hypertrophy. We found that carnosol can inhibit myocardial hypertrophy induced by PE stimulation, and the effect is very significant at 5 µM. Moreover, we demonstrated that 50 mg/kg of carnosol protect against cardiac hypertrophy and fibrosis induced by TAC surgery in mice. Mechanically, we proved that the inhibitory effect of carnosol on cardiac hypertrophy depends on its regulation on the phosphorylation activation of AMPK. In conclusion, our study suggested that carnosol may be a novel drug component for the treatment of pathological cardiac hypertrophy.

Targeting histone deacetylase in cardiac diseases.

Histone deacetylases (HDAC) catalyze the removal of acetylation modifications on histones and non-histone proteins, which regulates gene expression and other cellular processes. HDAC inhibitors (HDACi), approved anti-cancer agents, emerge as a potential new therapy for heart diseases. Cardioprotective effects of HDACi are observed in many preclinical animal models of heart diseases. Genetic mouse models have been developed to understand the role of each HDAC in cardiac functions. Some of the findings are controversial. Here, we provide an overview of how HDACi and HDAC impact cardiac functions under physiological or pathological conditions. We focus on in vivo studies of zinc-dependent classical HDACs, emphasizing disease conditions involving cardiac hypertrophy, myocardial infarction (MI), ischemic reperfusion (I/R) injury, and heart failure. In particular, we review how non-biased omics studies can help our understanding of the mechanisms underlying the cardiac effects of HDACi and HDAC.

Fenofibrate reduces cardiac remodeling by mitochondrial dynamics preservation in a renovascular model of cardiac hypertrophy.

Fenofibrate, a PPAR-α agonist clinically used to lower serum lipid levels, reduces cardiac remodeling and improves cardiac function. However, its mechanism of action is not completely elucidated. In this study we examined the effect of fenofibrate on mitochondria in a rat model of renovascular hypertension, focusing on mediators controlling mitochondrial dynamics and autophagy. Rats with two-kidney one-clip (2K1C) hypertension were treated with fenofibrate 150 mg/kg/day (2K1C-FFB) or vehicle (2K1C-VEH) for 8 weeks. Systolic blood pressure and cardiac functional were in-vivo assessed, while cardiomyocyte size and protein expression of mediators of cardiac hypertrophy and mitochondrial dynamics were ex-vivo examined by histological and Western blot analyses. Fenofibrate treatment counteracted the development of hypertension and the increase of left ventricular mass, relative wall thickness and cross-sectional area of cardiomyocytes. Furthermore, fenofibrate re-balanced the expression Mfn2, Drp1 and Parkin, regulators of fusion, fission, mitophagy respectively. Regarding autophagy, the LC3-II/LC3-I ratio was increased in 2K1C-VEH and 2K1C-FFB, whereas the autophagy was increased only in 2K1C-FFB. In cultured H9C2 cardiomyoblasts, fenofibrate reversed the Ang II-induced mRNA up-regulation of hypertrophy markers Nppa and Myh7, accumulation of reactive oxygen species and depolarization of the mitochondrial membrane exerting protection mediated by up-regulation of the Uncoupling protein 2. Our results indicate that fenofibrate acts directly on cardiomyocytes and counteracts the pressure overload-induced cardiac maladaptive remodeling. This study reveals a so far hidden mechanism involving mitochondrial dynamics in the beneficial effects of fenofibrate, support its repurposing for the treatment of cardiac hypertrophy and provide new potential targets for its pharmacological function.

Histone methyltransferase MLL4 protects against pressure overload-induced heart failure via a THBS4-mediated protection in ER stress.

Pressure overload-induced pathological cardiac hypertrophy eventually leads to heart failure (HF). Unfortunately, lack of effective targeted therapies for HF remains a challenge in clinical management. Mixed-lineage leukemia 4 (MLL4) is a member of the SET family of histone methyltransferase enzymes, which possesses histone H3 lysine 4 (H3K4)-specific methyltransferase activity. However, whether and how MLL4 regulates cardiac function is not reported in adult HF. Here we report that MLL4 is required for endoplasmic reticulum (ER) stress homeostasis of cardiomyocytes and protective against pressure overload-induced cardiac hypertrophy and HF. We observed that MLL4 is increased in the heart tissue of HF mouse model and HF patients. The cardiomyocyte-specific deletion of Mll4 (Mll4-cKO) in mice leads to aggravated ER stress and cardiac dysfunction following pressure overloading. MLL4 knockdown neonatal rat cardiomyocytes (NRCMs) also display accelerated decompensated ER stress and hypertrophy induced by phenylephrine (PE). The combined analysis of Cleavage Under Targets and Tagmentation sequencing (CUT&Tag-seq) and RNA sequencing (RNA-seq) data reveals that, silencing of Mll4 alters the chromatin landscape for H3K4me1 modification and gene expression patterns in NRCMs. Interestingly, the deficiency of MLL4 results in a marked reduction of H3K4me1 and H3K27ac occupations on Thrombospondin-4 (Thbs4) gene loci, as well as Thbs4 gene expression. Mechanistically, MLL4 acts as a transcriptional activator of Thbs4 through mono-methylation of H3K4 and further regulates THBS4-dependent ER stress response, ultimately plays a role in HF. Our study indicates that pharmacologically targeting MLL4 and ER stress might be a valid therapeutic approach to protect against cardiac hypertrophy and HF.

Artesunate attenuates isoprenaline induced cardiac hypertrophy in rats via SIRT1 inhibiting NF-κB activation.

Cardiac Hypertrophy is an adaptive response of the body to physiological and pathological stimuli, which increases cardiomyocyte size, thickening of cardiac muscles and progresses to heart failure. Downregulation of SIRT1 in cardiomyocytes has been linked with the pathogenesis of cardiac hypertrophy. The present study aimed to investigate the effect of Artesunate against isoprenaline induced cardiac hypertrophy in rats via SIRT1 inhibiting NF-κB activation. Experimental cardiac hypertrophy was induced in rats by subcutaneous administration of isoprenaline (5 mg/kg) for 14 days. Artesunate was administered simultaneously for 14 days at a dose of 25 mg/kg and 50 mg/kg. Artesunate administration showed significant dose dependent attenuation in mean arterial pressure, electrocardiogram, hypertrophy index and left ventricular wall thickness compared to the disease control group. It also alleviated cardiac injury biomarkers and oxidative stress. Histological observation showed amelioration of tissue injury in the artesunate treated groups compared to the disease control group. Further, artesunate treatment increased SIRT1 expression and decreased NF-kB expression in the heart. The results of the study show the cardioprotective effect of artesunate via SIRT1 inhibiting NF-κB activation in cardiomyocytes.

Compound 3K attenuates isoproterenol-induced cardiac hypertrophy by inhibiting pyruvate kinase M2 (PKM2) pathway.

AIM: Chronic sympathetic stimulation has been identified as a primary factor in the pathogenesis of cardiac hypertrophy (CH). However, there is no appropriate treatment available for the management of CH. Recently, it has been revealed that pyruvate kinase M2 (PKM2) plays a significant role in cardiac remodeling, fibrosis, and hypertrophy. However, the therapeutic potential of selective PKM2 inhibitor has not yet been explored in cardiac hypertrophy. Thus, in the current study, we have studied the cardioprotective potential of Compound 3K, a selective PKM2 inhibitor in isoproterenol-induced CH model. METHODS: To induce cardiac hypertrophy, male Wistar rats were subcutaneously administered isoproterenol (ISO, 5 mg/kg/day) for 14 days. Compound 3K at dosages of 2 and 4 mg/kg orally was administered to ISO-treated rats for 14 days to explore its effects on various parameters like ECG, ventricular functions, hypertrophic markers, histology, inflammation, and protein expression were performed. RESULTS: Fourteen days administration of ISO resulted in the induction of CH, which was evidenced by alterations in ECG, ventricular dysfunctions, increase in hypertrophy markers, and fibrosis. The immunoblotting of hypertrophy heart revealed the significant rise in PKM2 and reduction in PKM1 protein expression. Treatment with Compound 3K led to downregulation of PKM2 and upregulation of PKM1 protein expression. Compound 3K showed cardioprotective effects by improving ECG, cardiac functions, hypertrophy markers, inflammation, and fibrosis. Further, it also reduced cardiac expression of PKM2-associated splicing protein, HIF-1α, and caspase-3. CONCLUSION: Our findings suggest that Compound 3K has a potential cardioprotective effect via PKM2 inhibition in isoproterenol-induced CH.

Up-regulation of BRD4 contributes to gestational diabetes mellitus-induced cardiac hypertrophy in offspring by promoting mitochondria dysfunction in sex-independent manner.

Gestational diabetes mellitus (GDM) is associated with cardiovascular disease in postnatal life. The current study tested the hypothesis that GDM caused the cardiac hypertrophy in fetal (ED18.5), postnatal day 7 (PD7), postnatal day 21 (PD21) and postnatal day 90 (PD90) offspring by upregulation of BRD4 and mitochondrial dysfunction. Pregnant mice were divided into control and GDM groups. Hearts were isolated from ED18.5, PD7, PD21 and PD90. GDM increased the body weight (BW) and heart weight (HW) in ED18.5 and PD7, but not PD21 and PD90 offspring. However, HW/BW ratio was increased in all ages of GDM offspring compared to control group. Electron microscopy showed disorganized myofibrils, mitochondrial swelling, vacuolization, and cristae disorder in GDM offspring. GDM resulted in myocardial hypertrophy in offspring, which persisted from fetus to adult in a sex-independent manner. Echocardiography analysis revealed that GDM caused diastolic dysfunction, but had no effect on systolic function. Meanwhile, myocardial BRD4 was significantly upregulated in GDM offspring and BRD4 inhibition by JQ1 alleviated GDM-induced myocardial hypertrophy in offspring. Co-immunoprecipitation showed that BRD4 interacted with DRP1 and there was an increase of BRD4 and DRP1 interaction in GDM offspring. Furthermore, GDM caused the accumulation of damaged mitochondria in hearts from all ages of offspring, including mitochondrial fusion fission imbalance (upregulation of DRP1, and downregulation of MFN1, MFN2 and OPA1) and myocardial mitochondrial ROS accumulation, which was reversed by JQ1. These results suggested that the upregulation of BRD4 is involved in GDM-induced myocardial hypertrophy in the offspring through promoting mitochondrial damage in a gender-independent manner.

Beneficial Effects of Exercise on Hypertension-Induced Cardiac Hypertrophy in Adolescents and Young Adults.

PURPOSE OF REVIEW: Hypertension-induced cardiac hypertrophy is widely known as a major risk factor for increased cardiovascular morbidity and mortality. Although exercise is proven to exert overall beneficial effects on hypertension and hypertension-induced cardiac hypertrophy, there are some concerns among providers about potential adverse effects induced by intense exercise, especially in hypertensive athletes. We will overview the underlying mechanisms of physiological and pathological hypertrophy and delineate the beneficial effects of exercise in young people with hypertension and consequent hypertrophy. RECENT FINDINGS: Multiple studies have demonstrated that exercise training, both endurance and resistance types, reduces blood pressure and ameliorates hypertrophy in hypertensives, but certain precautions are required for hypertensive athletes when allowing competitive sports: Elevated blood pressure should be controlled before allowing them to participate in high-intensity exercise. Non-vigorous and recreational exercise are always recommended to promote cardiovascular health. Exercise-induced cardiac adaptation is a benign and favorable response that reverses or attenuates pathological cardiovascular remodeling induced by persistent hypertension. Exercise is the most effective nonpharmacological treatment for hypertensive individuals. Distinction between recreational-level exercise and competitive sports should be recognized by medical providers when allowing sports participation for adolescents and young adults.

Vincristine attenuates isoprenaline-induced cardiac hypertrophy in male Wistar rats via suppression of ROS/NO/NF-қB signalling pathways.

Vincristine (VCR), a vinca alkaloid with anti-tumor and anti-oxidant properties, is acclaimed to possess cardioprotective action. However, the molecular mechanism underlying this protective effect remains unknown. This study investigated the effects of VCR on isoprenaline (ISO), a beta-adrenergic receptor agonist, induced cardiac hypertrophy in male Wistar rats. Animals were pre-treated with ISO (1 mg/kg) intraperitoneally for 14 days before VCR (25 µg/kg) intraperitoneal injection from days 1 to 28. Thereafter, mechanical, and electrical activities of the hearts of the rats were measured using a non-invasive blood pressure monitor and an electrocardiograph, respectively. After which, the heart was homogenized, and supernatants were assayed for contractile proteins: endothelin-1, cardiac troponin-1, angiotensin-II, and creatine kinase-MB, with markers of oxidative/nitrergic stress (SOD, CAT, MDA, GSH, and NO), inflammation (TNF-a and IL-6, NF-kB), and caspase-3 indicative of VCR reduced elevated blood pressure and reversed the abnormal electrocardiogram. ISO-induced increased endothelin-1, cardiac troponin-1, angiotensin-II, and creatine phosphokinase-MB, which were reversed by VCR. ISO also increased TNF-α, IL-6, NF-kB expression with increased caspase-3-mediated apoptosis in the heart. However, VCR reduced ISO-induced inflammation and apoptosis, with improved endogenous antioxidant agents (GSH, SOD, CAT) relative to ISO controls. Moreso, VCR, protected against ISO-induced histoarchitectural degeneration of cardiac myofibre. The result of this study revealed that VCR treatment significantly reverses ISO-induced cardiac hypertrophic phenotypes, via mechanisms connected to improved levels of proteins involved in excitation-contraction, and suppression of oxido-inflammatory and apoptotic pathways.

Inhibition of Cholesteryl Ester Transfer Protein Contributes to the Protection of Ginsenoside Re Against Isoproterenol-Induced Cardiac Hypertrophy.

Background and objectives Ginsenoside Re (Re), a protopanaxatriol-type saponin extracted from ginseng, is known to have potential cardioprotective effects; however, the mechanisms of Re in improving cardiac hypertrophy have not been fully elucidated. This study aimed to investigate the therapeutic effects and underlying mechanism of Re on isoproterenol (ISO)-induced cardiac hypertrophy in vivo and in vitro. Methods Rats were intraperitoneally injected with ISO 30 mg/kg thrice daily for 14 consecutive days to induce cardiac hypertrophy, and these rats were treated with atorvastatin (ATC, 20 mg/kg) or Re (20 mg/kg or 40 mg/kg) once daily for three days in advance until the end of the experiment. Heart weight index, hematoxylin and eosin staining, and hypertrophy-related fetal gene expression were measured to evaluate the effect of Re on cardiac hypertrophy in vivo. Meanwhile, the rat H9c2 cardiomyocyte hypertrophy model was induced by ISO 10 µM for 24 hours. Cell surface area and hypertrophy-related fetal gene expression were determined to assess the effect of Re on ISO-induced cardiomyocyte hypertrophy in vitro. The levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in both serum and cardiomyocytes were detected by enzymatic colorimetric assays. Furthermore, we chose cholesteryl ester transfer protein (CETP) as a target to explore the influence of Re on CETP expression in vivo and in vitro through real-time polymerase chain reaction, western blot, and enzyme-linked immunosorbent assay. Results Intraperitoneal administration of ISO into rats resulted in increases in cross-sectional cardiomyocyte area, the ratio of heart weight to body weight, the ratio of left ventricular weight to body weight, and the ratio of right ventricular weight to body weight, as well as reactivation of fetal genes; however, treatment with Re or ATC ameliorated most of these hypertrophic responses. Similarly, Re pronouncedly alleviated ISO-induced cardiomyocyte hypertrophy, as evidenced by a decreased cell surface area and downregulation of fetal genes. Moreover, our in vivo and in vitro data revealed that Re reduced TC, TG, and LDL-C levels, and enhanced HDL-C levels. Re improved cardiac hypertrophy mainly associated with the inhibition of mRNA level and protein expression of CETP, to an extent comparable to that of the classical CETP inhibitor, anacetrapib. Conclusions Our research found that CETP inhibition contributes to the protection of Re against ISO-induced cardiac hypertrophy, which provides evidence for the application of Re for cardiovascular disease treatments.

Treatment with αvß3-integrin-specific 29P attenuates pressure-overload induced cardiac remodelling after transverse aortic constriction in mice.

Heart failure remains one of the largest clinical burdens globally, with little to no improvement in the development of disease-eradicating therapeutics. Integrin targeting has been used in the treatment of ocular disease and cancer, but little is known about its utility in the treatment of heart failure. Here we sought to determine whether the second generation orally available, αvß3-specific RGD-mimetic, 29P , was cardioprotective. Male mice were subjected to transverse aortic constriction (TAC) and treated with 50 µg/kg 29P or volume-matched saline as Vehicle control. At 3 weeks post-TAC, echocardiography showed that 29P treatment significantly restored cardiac function and structure indicating the protective effect of 29P treatment in this model of heart failure. Importantly, 29P treatment improved cardiac function giving improved fractional shortening, ejection fraction, heart weight and lung weight to tibia length fractions, together with partial restoration of Ace and Mme levels, as markers of the TAC insult. At a tissue level, 29P reduced cardiomyocyte hypertrophy and interstitial fibrosis, both of which are major clinical features of heart failure. RNA sequencing identified that, mechanistically, this occurred with concomitant alterations to genes involved molecular pathways associated with these processes such as metabolism, hypertrophy and basement membrane formation. Overall, targeting αvß3 with 29P provides a novel strategy to attenuate pressure-overload induced cardiac hypertrophy and fibrosis, providing a possible new approach to heart failure treatment.

lncRNA Gm20257 alleviates pathological cardiac hypertrophy by modulating the PGC-1α-mitochondrial complex IV axis.

Pathological cardiac hypertrophy, a major contributor to heart failure, is closely linked to mitochondrial function. The roles of long noncoding RNAs (lncRNAs), which regulate mitochondrial function, remain largely unexplored in this context. Herein, a previously unknown lncRNA, Gm20257, was identified. It markedly increased under hypertrophic stress in vivo and in vitro. The suppression of Gm20257 by using small interfering RNAs significantly induced cardiomyocyte hypertrophy. Conversely, the overexpression of Gm20257 through plasmid transfection or adeno-associated viral vector-9 mitigated angiotensin II-induced hypertrophic phenotypes in neonatal mouse ventricular cells or alleviated cardiac hypertrophy in a mouse TAC model respectively, thus restoring cardiac function. Importantly, Gm20257 restored mitochondrial complex IV level and enhanced mitochondrial function. Bioinformatics prediction showed that Gm20257 had a high binding score with peroxisome proliferator-activated receptor coactivator-1 (PGC-1α), which could increase mitochondrial complex IV. Subsequently, Western blot analysis results revealed that Gm20257 substantially affected the expression of PGC-1α. Further analyses through RNA immunoprecipitation and immunoblotting following RNA pull-down indicated that PGC-1α was a direct downstream target of Gm20257. This interaction was demonstrated to rescue the reduction of mitochondrial complex IV induced by hypertrophic stress and promote the generation of mitochondrial ATP. These findings suggest that Gm20257 improves mitochondrial function through the PGC-1α-mitochondrial complex IV axis, offering a novel approach for attenuating pathological cardiac hypertrophy.

Liraglutide ameliorates TAC-induced cardiac hypertrophy and heart failure by upregulating expression level of ANP expression.

Recent studies have underscored the cardioprotective properties of liraglutide. This research explores its impact on cardiac hypertrophy and heart failure following transverse aortic constriction (TAC). We found that liraglutide administration markedly ameliorated cardiac hypertrophy, fibrosis, and function. These benefits correlated with increased ANP expression and reduced activity in the calcineurin A/NFATc3 signaling pathway. Moreover, liraglutide mitigated ER stress and cardiomyocyte apoptosis, and enhanced autophagy. Notably, the positive effects of liraglutide diminished when co-administered with A71915, an ANP inhibitor, suggesting that ANP upregulation is critical to its cardioprotective mechanism.

Overexpression of macrophage migration inhibitory factor protects against pressure overload-induced cardiac hypertrophy through regulating the miR-29b-3p/HBP1 axis.

Cardiac hypertrophy is an adaptive response to stressors such as high cardiac workload, which might lead to abnormal cardiac function and heart failure. Previous studies have indicated that macrophage migration inhibitory factor (MIF) might play a protective role in cardiac hypertrophy. Here, we aimed to illustrate the mechanism of MIF in protecting against pressure overload-induced cardiac hypertrophy. Transverse aortic constriction (TAC) mouse model was established and we found that overexpression of MIF protected against pressure overload-induced cardiac hypotrophy in TAC treated mice, as evidenced by significantly decreased the heart weight. In addition, transthoracic echocardiography showed that overexpression of MIF restored ejection fraction in TAC-treated mice. While TAC treatment resulted in a much larger cardiomyocyte size in mice, MIF overexpression notably decreased the cardiomyocyte size. Next, we demonstrated that MIF overexpression promoted the expression of miR-29b-3p which further downregulated the expression of its downstream target HMG box protein 1 (HBP1). Overexpression of HBP1 reversed the effect of MIF in alleviating Ang-II induced oxidative stress in cardiomyocytes. In conclusion, our findings suggest that MIF could attenuate pressure overload-induced cardiac hypertrophy through regulating the miR-29b-3p/HBP1 axis.

Sodium-glucose exchanger 2 inhibitor canagliflozin promotes mitochondrial metabolism and alleviates salt-induced cardiac hypertrophy via preserving SIRT3 expression.

INTRODUCTION: Excess salt intake is not only an independent risk factor for heart failure, but also one of the most important dietary factors associated with cardiovascular disease worldwide. Metabolic reprogramming in cardiomyocytes is an early event provoking cardiac hypertrophy that leads to subsequent cardiovascular events upon high salt loading. Although SGLT2 inhibitors, such as canagliflozin, displayed impressive cardiovascular health benefits, whether SGLT2 inhibitors protect against cardiac hypertrophy-related metabolic reprogramming upon salt loading remain elusive. OBJECTIVES: To investigate whether canagliflozin can improve salt-induced cardiac hypertrophy and the underlying mechanisms. METHODS: Dahl salt-sensitive rats developed cardiac hypertrophy by feeding them an 8% high-salt diet, and some rats were treated with canagliflozin. Cardiac function and structure as well as mitochondrial function were examined. Cardiac proteomics, targeted metabolomics and SIRT3 cardiac-specific knockout mice were used to uncover the underlying mechanisms. RESULTS: In Dahl salt-sensitive rats, canagliflozin showed a potent therapeutic effect on salt-induced cardiac hypertrophy, accompanied by lowered glucose uptake, reduced accumulation of glycolytic end-products and improved cardiac mitochondrial function, which was associated with the recovery of cardiac expression of SIRT3, a key mitochondrial metabolic regulator. Cardiac-specific knockout of SIRT3 not only exacerbated salt-induced cardiac hypertrophy but also abolished the therapeutic effect of canagliflozin. Mechanistically, high salt intake repressed cardiac SIRT3 expression through a calcium-dependent epigenetic modifications, which could be blocked by canagliflozin by inhibiting SGLT1-mediated calcium uptake. SIRT3 improved myocardial metabolic reprogramming by deacetylating MPC1 in cardiomyocytes exposed to pro-hypertrophic stimuli. Similar to canagliflozin, the SIRT3 activator honokiol also exerted therapeutic effects on cardiac hypertrophy. CONCLUSION: Cardiac mitochondrial dysfunction caused by SIRT3 repression is a critical promotional determinant of metabolic pattern switching underlying salt-induced cardiac hypertrophy. Improving SIRT3-mediated mitochondrial function by SGLT2 inhibitors-mediated calcium handling would represent a therapeutic strategy against salt-related cardiovascular events.

A murine model of hypertensive heart disease in older women.

We propose a new mouse (C57Bl6/J) model combining several features of heart failure with preserved ejection fraction encountered in older women, including hypertension from Angiotensin II infusion (AngII), menopause, and advanced age. To mimic menopause, we delayed ovariectomy (Ovx) at 12 months of age. We also studied the effects of AngII infusion for 28 days in younger animals and the impact of losing gonadal steroids earlier in life. We observed that AngII effects on heart morphology were different in younger and adult mice (3- and 12-month-old; 20 and 19% increase in heart weight. P < 0.01 for both) than in older animals (24-month-old; 6%; not significant). Ovariectomy at 12 months restored the hypertrophic response to AngII in elderly females (23%, p = 0.0001). We performed a bulk RNA sequencing study of the left ventricle (LV) and left atrial gene expression in elderly animals, controls, and Ovx. AngII modulated (|Log2 fold change| ≥ 1) the LV expression of 170 genes in control females and 179 in Ovx ones, 64 being shared. In the left atrium, AngII modulated 235 genes in control females and 453 in Ovx, 140 shared. We observed many upregulated genes associated with the extracellular matrix regulation in both heart chambers. Many of these upregulated genes were shared between the ventricle and the atrium as well as in control and Ovx animals, namely for the most expressed Ankrd1, Nppb, Col3a1, Col1a1, Ctgf Col8a1, and Cilp. Several circadian clock LV genes were modulated differently by AngII between control and Ovx females (Clock, Arntl, Per2, Cry2, and Ciart). In conclusion, sex hormones, even in elderly female mice, modulate the heart's hypertrophic response to AngII. Our study identifies potential new markers of hypertensive disease in aging female mice and possible disturbances of their cardiac circadian clock.

A pseudo-targeted metabolomics for discovery of potential biomarkers of cardiac hypertrophy in rats.

Cardiac hypertrophy (CH) is one of the stages in the occurrence and development of severe cardiovascular diseases, and exploring its biomarkers is beneficial for delaying the progression of severe cardiovascular diseases. In this research, we established a comprehensive and highly efficient pseudotargeted metabolomics method, which demonstrated a superior capacity to identify differential metabolites when compared to traditionaluntargeted metabolomics. The intra/inter-day precision and reproducibility results proved the method is reliable and precise. The established method was then applied to seek the potential differentiated metabolic biomarkers of cardiac hypertrophy (CH) rats, and oxylipins, phosphorylcholine (PC), lysophosphatidylcholine (LysoPC), lysophosphatidylethanolamine (LysoPE), Krebs cycle intermediates, carnitines, amino acids, and bile acids were disclosed to be the possible differentiate components. Their metabolic pathway analysis revealed that the potential metabolic alterations in CH rats were mainly associated with phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, arachidonic acid metabolism, citrate cycle, glyoxylate and dicarboxylate metabolism, and tyrosine metabolism. In sum, this research provided a comprehensiveand reliable LC-MS/MS MRM platform for pseudo-targeted metabolomics investigation of disease condition, and some interesting potential biomarkers were disclosed for CH, which merit further exploration in the future.

Effect of Stanozolol and/or Cannabis Abuse on Hypertrophic Mechanism and Oxidative Stress of Male Albino Rat Cardiac Tissue in Relation to Exercise: A Sport Abuse Practice.

Adolescents commonly co-abuse many drugs including anabolic androgenic steroids either they are athletes or non-athletes. Stanozolol is the major anabolic used in recent years and was reported grouped with cannabis. The current study aimed at evaluating the biochemical and histopathological changes related to the hypertrophic effects of stanozolol and/or cannabis whether in condition of exercise practice or sedentary conditions. Adult male Wistar albino rats received either stanozolol (5 mg/kg, s.c), cannabis (10 mg/kg, i.p.), and a combination of both once daily for two months. Swimming exercise protocol was applied as a training model. Relative heart weight, oxidative stress biomarkers, cardiac tissue fibrotic markers were evaluated. Left ventricular morphometric analysis and collagen quantification was done. The combined treatment exhibited serious detrimental effects on the heart tissues. It increased heart tissue fibrotic markers (Masson's trichrome stain (p < 0.001), cardiac COL3 (p < 0.0001), and VEGF-A (p < 0.05)), lowered heart glutathione levels (p < 0.05) and dramatically elevated oxidative stress (increased malondialdehyde (p < 0.0001) and 8-OHDG (p < 0.0001)). Training was not ameliorating for the observed effects. Misuse of cannabis and stanozolol resulted in more hypertrophic consequences of the heart than either drug alone, which were at least largely assigned to oxidative stress, heart tissue fibrotic indicators, histological alterations, and morphometric changes.