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.

Deleting the ribosomal prolyl hydroxylase OGFOD1 protects mice against diet-induced obesity and insulin resistance.

Type 2 diabetes predisposes patients to heart disease, which is the primary cause of death across the globe. Type 2 diabetes often accompanies obesity and is defined by insulin resistance and abnormal glucose handling. Insulin resistance impairs glucose uptake and results in hyperglycemia, which damages tissues such as kidneys, liver, and heart. 2-oxoglutarate (2-OG)- and iron-dependent oxygenases (2-OGDOs), a family of enzymes regulating various aspects of cellular physiology, have been studied for their role in obesity and diet-induced insulin resistance. However, nothing is known of the 2-OGDO family member 2-oxoglutarate and iron-dependent prolyl hydroxylase domain containing protein 1 (OGFOD1) in this setting. OGFOD1 deletion leads to protection in cardiac ischemia-reperfusion injury and cardiac hypertrophy, which are two cardiac events that can lead to heart failure. Considering the remarkable correlation between heart disease and diabetes, the cardioprotection observed in OGFOD1-knockout mice led us to challenge these knockouts with high-fat diet. Wildtype mice fed a high-fat diet developed diet-induced obesity, insulin resistance, and glucose intolerance, but OGFOD1 knockout mice fed this same diet were resistant to diet-induced obesity and insulin resistance. These results support OGFOD1 down-regulation as a strategy for preventing obesity and insulin handling defects.

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.

Therapeutic Inhibition of LincRNA-p21 Protects Against Cardiac Hypertrophy.

BACKGROUND: Cardiac hypertrophy is an adaptive response to pressure overload aimed at maintaining cardiac function. However, prolonged hypertrophy significantly increases the risk of maladaptive cardiac remodeling and heart failure. Recent studies have implicated long noncoding RNAs in cardiac hypertrophy and cardiomyopathy, but their significance and mechanism(s) of action are not well understood. METHODS: We measured lincRNA-p21 RNA and H3K27ac levels in the hearts of dilated cardiomyopathy patients. We assessed the functional role of lincRNA-p21 in basal and surgical pressure-overload conditions using loss-of-function mice. Genome-wide transcriptome analysis revealed dysregulated genes and pathways. We labeled proteins in proximity to full-length lincRNA-p21 using a novel BioID2-based system. We immunoprecipitated lincRNA-p21-interacting proteins and performed cell fractionation, ChIP-seq (chromatin immunoprecipitation followed by sequencing), and co-immunoprecipitation to investigate molecular interactions and underlying mechanisms. We used GapmeR antisense oligonucleotides to evaluate the therapeutic potential of lincRNA-p21 inhibition in cardiac hypertrophy and associated heart failure. RESULTS: lincRNA-p21 was induced in mice and humans with cardiomyopathy. Global and cardiac-specific lincRNA-p21 knockout significantly suppressed pressure overload-induced ventricular wall thickening, stress marker elevation, and deterioration of cardiac function. Genome-wide transcriptome analysis and transcriptional network analysis revealed that lincRNA-p21 acts in trans to stimulate the NFAT/MEF2 (nuclear factor of activated T cells/myocyte enhancer factor-2) pathway. Mechanistically, lincRNA-p21 is bound to the scaffold protein KAP1 (KRAB-associated protein-1). lincRNA-p21 cardiac-specific knockout suppressed stress-induced nuclear accumulation of KAP1, and KAP1 knockdown attenuated cardiac hypertrophy and NFAT activation. KAP1 positively regulates pathological hypertrophy by physically interacting with NFATC4 to promote the overactive status of NFAT/MEF2 signaling. GapmeR antisense oligonucleotide depletion of lincRNA-p21 similarly inhibited cardiac hypertrophy and adverse remodeling, highlighting the therapeutic potential of inhibiting lincRNA-p21. CONCLUSIONS: These findings advance our understanding of the functional significance of stress-induced long noncoding RNA in cardiac hypertrophy and demonstrate the potential of lincRNA-p21 as a novel therapeutic target for cardiac hypertrophy and subsequent heart failure.

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.

Aspirin and Celecoxib Regulate Notch1/Hes1 Pathway to Prevent Pressure Overload-Induced Myocardial Hypertrophy.

This study aimed to investigate the molecular mechanisms underlying the protective effects of cyclooxygenase (cox) inhibitors against myocardial hypertrophy.Rat H9c2 cardiomyocytes were induced by mechanical stretching. SD rats underwent transverse aortic constriction to induce pressure overload myocardial hypertrophy. Rats were subjected to echocardiography and tail arterial pressure in 12W. qPCR and western blot were used to detect the expression of Notch-related signaling. The inflammatory factors were tested by ELISA in serum, heart tissue, and cell culture supernatant.Compared with control, levels of pro-inflammatory cytokines IL-6, TNF-α, and IL-1ß were increased and anti-inflammatory cytokine IL-10 was reduced in myocardial tissues and serum of rat models. Levels of Notch1 and Hes1 were reduced in myocardial tissues. However, cox inhibitor treatment (aspirin and celecoxib), the improvement of exacerbated myocardial hypertrophy, fibrosis, dysfunction, and inflammation was parallel to the activation of Notch1/Hes1 pathway. Moreover, in vitro experiments showed that, in cardiomyocyte H9c2 cells, application of ~20% mechanical stretching activated inflammatory mediators (IL-6, TNF-α, and IL-1ß) and hypertrophic markers (ANP and BNP). Moreover, expression levels of Notch1 and Hes1 were decreased. These changes were effectively alleviated by aspirin and celecoxib.Cox inhibitors may protect heart from hypertrophy and inflammation possibly via the Notch1/Hes1 signaling pathway.

Qiangxinyin formula protects against isoproterenol-induced cardiac hypertrophy.

Heart failure is a life-threatening cardiovascular disease and characterized by cardiac hypertrophy, inflammation and fibrosis. The traditional Chinese medicine formula Qiangxinyin (QXY) is effective for the treatment of heart failure while the underlying mechanism is not clear. This study aims to identify the active ingredients of QXY and explore its mechanisms protecting against cardiac hypertrophy. We found that QXY significantly protected against isoproterenol (ISO)-induced cardiac hypertrophy and dysfunction in zebrafish. Eight compounds, including benzoylmesaconine (BMA), atractylenolide I (ATL I), icariin (ICA), quercitrin (QUE), psoralen (PRN), kaempferol (KMP), ferulic acid (FA) and protocatechuic acid (PCA) were identified from QXY. PRN, KMP and icaritin (ICT), an active pharmaceutical ingredient of ICA, prevented ISO-induced cardiac hypertrophy and dysfunction in zebrafish. In H9c2 cardiomyocyte treated with ISO, QXY significantly blocked the calcium influx, reduced intracellular lipid peroxidative product MDA, stimulated ATP production and increased mitochondrial membrane potential. QXY also inhibited ISO-induced cardiomyocyte hypertrophy and cytoskeleton reorganization. Mechanistically, QXY enhanced the phosphorylation of Smad family member 2 (SMAD2) and myosin phosphatase target subunit-1 (MYPT1), and suppressed the phosphorylation of myosin light chain (MLC). In conclusion, PRN, KMP and ICA are the main active ingredients of QXY that protect against ISO-induced cardiac hypertrophy and dysfunction largely via the blockage of calcium influx and inhibition of mitochondrial dysfunction as well as cytoskeleton reorganization.

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

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

RyR2 Stabilizer Attenuates Cardiac Hypertrophy by Downregulating TNF-α/NF-κB/NLRP3 Signaling Pathway through Inhibiting Calcineurin.

The effect of Ryanodine receptor2 (RyR2) and its stabilizer on cardiac hypertrophy is not well known. C57/BL6 mice underwent transverse aortic contraction (TAC) or sham surgery were administered dantrolene, the RyR2 stabilizer, or control drug. Dantrolene significantly alleviated TAC-induced cardiac hypertrophy in mice, and RNA sequencing was performed implying calcineurin/NFAT3 and TNF-α/NF-κB/NLRP3 as critical signaling pathways. Further expression analysis and Western blot with heart tissue as well as neonatal rat cardiomyocyte (NRCM) model confirmed dantrolene decreases the activation of calcineurin/NFAT3 signaling pathway and TNF-α/NF-κB/NLRP3 signaling pathway, which was similar to FK506 and might be attenuated by calcineurin overexpression. The present study shows for the first time that RyR2 stabilizer dantrolene attenuates cardiac hypertrophy by inhibiting the calcineurin, therefore downregulating the TNF-α/NF-κB/NLRP3 pathway.

Calorie restriction anti-hypertrophic effects are associated with improved mitochondrial content, blockage of Ca2+-induced mitochondrial damage, and lower reverse electron transport-mediated oxidative stress.

Calorie restriction is a nutritional intervention that reproducibly protects against the maladaptive consequences of cardiovascular diseases. Pathological cardiac hypertrophy leads to cellular growth, dysfunction (with mitochondrial dysregulation), and oxidative stress. The mechanisms behind the cardiovascular protective effects of calorie restriction are still under investigation. In this study, we show that this dietetic intervention prevents cardiac protein elevation, avoids fetal gene reprogramming (atrial natriuretic peptide), and blocks the increase in heart weight per tibia length index (HW/TL) seen in isoproterenol-induced cardiac hypertrophy. Our findings suggest that calorie restriction inhibits cardiac pathological growth while also lowering mitochondrial reverse electron transport-induced hydrogen peroxide formation and improving mitochondrial content. Calorie restriction also attenuated the opening of the Ca2+-induced mitochondrial permeability transition pore. We also found that calorie restriction blocked the negative correlation of antioxidant enzymes (superoxide dimutase and glutatione peroxidase activity) and HW/TL, leading to the maintenance of protein sulphydryls and glutathione levels. Given the nature of isoproterenol-induced cardiac hypertrophy, we investigated whether calorie restriction could alter cardiac beta-adrenergic sensitivity. Using isolated rat hearts in a Langendorff system, we found that calorie restricted hearts have preserved beta-adrenergic signaling. In contrast, hypertrophic hearts (treated for seven days with isoproterenol) were insensitive to beta-adrenergic activation using isoproterenol (50 nM). Despite protecting against cardiac hypertrophy, calorie restriction did not alter the lack of responsiveness to isoproterenol in isolated hearts harvested from isoproterenol-treated rats. These results suggest (through a series of mitochondrial, oxidative stress, and cardiac hemodynamic studies) that calorie restriction possesses beneficial effects against hypertrophic cardiomyopathy.

Short Communication: Taurine Long-Term Treatment Prevents the Development of Cardiac Hypertrophy, and Premature Death in Hereditary Cardiomyopathy of the Hamster Is Sex-Independent.

Recently, we reported that during the hypertrophic phase (230 days old) of hereditary cardiomyopathy of the hamster (HCMH), short-term treatment (20 days) with 250 mg/kg/day of taurine prevents the development of hypertrophy in males but not in females. However, the mortality rate in non-treated animals was higher in females than in males. To verify whether the sex-dependency effect of taurine is due to the difference in the disease's progression, we treated the 230-day-old animals for a longer time period of 122 days. Our results showed that long-term treatment with low and high concentrations of taurine significantly prevents cardiac hypertrophy and early death in HCMH males (p < 0.0001 and p < 0.05, respectively) and females (p < 0.01 and p < 0.0001, respectively). Our results demonstrate that the reported sex dependency of short-term treatments with taurine is due to a higher degree of heart remodeling in females when compared to males and not to sex dependency. In addition, sex-dependency studies should consider the differences between the male and female progression of the disease. Thus, long-term taurine therapies are recommended to prevent remodeling and early death in hereditary cardiomyopathy.

Angiotensin-(1-7) Treatment Early in Life Prevents Cardiac Hypertrophy in Adult Hypertensive Rats.

ABSTRACT: Angiotensin (Ang)-(1-7) is a cardioprotective peptide of the renin-angiotensin system. Prepuberty has been considered as a later susceptible window of development, and stressful factors in this life phase can induce chronic diseases in adulthood. We aimed to investigate whether the treatment with Ang-(1-7) during the prepuberty could attenuate the development of hypertension and cardiac injury in adult spontaneously hypertensive rats (SHRs). SHRs were treated with Ang-(1-7) (24 µg/kg/h) from age 4 to 7 weeks. Systolic blood pressure was measured by tail-cuff plethysmography up to 17th week. Thereafter, echocardiography was performed, and the rats were euthanized for the collection of tissues and blood. Ang-(1-7) did not change the systolic blood pressure but reduced the septal and posterior wall thickness, and cardiomyocyte hypertrophy and fibrosis in SHR. In addition, Ang-(1-7) reduced the gene expression of atrial natriuretic peptide and brain natriuretic peptide, increased the metalloproteinase 9 expression, and reduced the extracellular signal-regulated kinases 1/2 phosphorylation. Ang-(1-7) also prevented the reduction of Mas receptor but did not change the protein expression of angiotensin-converting enzyme, angiotensin-converting enzyme 2, AT1, and AT2. The treatment with Ang-(1-7) decreased the malondialdehyde (MDA) levels and increased superoxide dismutase-1 and catalase activities and protein expression of catalase. Our findings demonstrate that the treatment of SHR with Ang-(1-7) for 3 weeks early in life promotes beneficial effects in the heart later in life, even without altering blood pressure, through mechanisms involving the reduction of oxidative stress and ERK1/2 phosphorylation. In addition, this study supports the prepuberty as an important programming window.

Empagliflozin mitigates cardiac hypertrophy through cardiac RSK/NHE-1 inhibition.

BACKGROUND: SGLT2i reduce cardiac hypertrophy, but underlying mechanisms remain unknown. Here we explore a role for serine/threonine kinases (STK) and sodium hydrogen exchanger 1(NHE1) activities in SGLT2i effects on cardiac hypertrophy. METHODS: Isolated hearts from db/db mice were perfused with 1 µM EMPA, and STK phosphorylation sites were examined using unbiased multiplex analysis to detect the most affected STKs by EMPA. Subsequently, hypertrophy was induced in H9c2 cells with 50 µM phenylephrine (PE), and the role of the most affected STK (p90 ribosomal S6 kinase (RSK)) and NHE1 activity in hypertrophy and the protection by EMPA was evaluated. RESULTS: In db/db mice hearts, EMPA most markedly reduced STK phosphorylation sites regulated by RSKL1, a member of the RSK family, and by Aurora A and B kinases. GO and KEGG analysis suggested that EMPA inhibits hypertrophy, cell cycle, cell senescence and FOXO pathways, illustrating inhibition of growth pathways. EMPA prevented PE-induced hypertrophy as evaluated by BNP and cell surface area in H9c2 cells. EMPA blocked PE-induced activation of NHE1. The specific NHE1 inhibitor Cariporide also prevented PE-induced hypertrophy without added effect of EMPA. EMPA blocked PE-induced RSK phosphorylation. The RSK inhibitor BIX02565 also suppressed PE-induced hypertrophy without added effect of EMPA. Cariporide mimicked EMPA's effects on PE-treated RSK phosphorylation. BIX02565 decreased PE-induced NHE1 activity, with no further decrease by EMPA. CONCLUSIONS: RSK inhibition by EMPA appears as a novel direct cardiac target of SGLT2i. Direct cardiac effects of EMPA exert their anti-hypertrophic effect through NHE-inhibition and subsequent RSK pathway inhibition.

Chlorogenic acid attenuates cardiac hypertrophy via up-regulating Sphingosine-1-phosphate receptor1 to inhibit endoplasmic reticulum stress.

AIMS: Cardiac hypertrophy, an adaptive response of the heart to stress overload, is closely associated with heart failure and sudden cardiac death. This study aimed to investigate the therapeutic effects of chlorogenic acid (CGA) on cardiac hypertrophy and elucidate the underlying mechanisms. METHODS AND RESULTS: To simulate cardiac hypertrophy, myocardial cells were exposed to isoproterenol (ISO, 10 µM). A rat model of ISO-induced cardiac hypertrophy was also established. The expression levels of cardiac hypertrophy markers, endoplasmic reticulum stress (ERS) markers, and apoptosis markers were measured using quantitative reverse transcription PCR and western blotting. The apoptosis level, size of myocardial cells, and heart tissue pathological changes were determined by terminal deoxynucleotidyl transferase dUTP nick-end labelling staining, immunofluorescence staining, haematoxylin and eosin staining, and Masson's staining. We found that CGA treatment decreased the size of ISO-treated H9c2 cells. Moreover, CGA inhibited ISO-induced up-regulation of cardiac hypertrophy markers (atrial natriuretic peptide, brain natriuretic peptide, and ß-myosin heavy chain), ERS markers (C/EBP homologous protein, glucose regulatory protein 78, and protein kinase R-like endoplasmic reticulum kinase), and apoptosis markers (bax and cleaved caspase-12/9/3) but increased the expression of anti-apoptosis marker bcl-2 in a dose-dependent way (0, 10, 50, and 100 µM). Knockdown of sphingosine-1-phosphate receptor 1 (S1pr1) reversed the protective effect of CGA on cardiac hypertrophy, ERS, and apoptosis in vitro (P < 0.05). CGA also restored ISO-induced inhibition on the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) signalling in H9c2 cells, while S1pr1 knockdown abolished these CGA-induced effects (P < 0.05). CGA (90 mg/kg/day, for six consecutive days) protected rats against cardiac hypertrophy in vivo (P < 0.05). CONCLUSIONS: CGA treatment attenuated ISO-induced ERS and cardiac hypertrophy by activating the AMPK/SIRT1 pathway via modulation of S1pr1.

Vitamin D Protects Against Cardiac Hypertrophy Through the Regulation of Mitochondrial Function in Aging Rats.

Cardiac aging is defined as mitochondrial dysfunction of the heart. Vitamin D (VitD) is an effective agent in ameliorating cardiovascular disorders. In this study, we indicated the protective effects of VitD against cardiac aging. Male Wistar rats were randomly divided into four groups: control (CONT), D-galactose (D-GAL): aged rats induced by D-GAL, D-GAL + Ethanol: aged rats treated with ethanol, and D-GAL + VitD aged rats treated with VitD. Aging was induced by D-GAL at 150 mg/kg via intraperitoneal injection for 8 weeks. Aged rats were treated with VitD (D-GAL + VitD) by gavage for 8 weeks. The serum samples were used to evaluate biochemical factors, and heart tissues were assessed to determine oxidative stress and gene expression. The D-GAL rats exhibited cardiac hypertrophy, which was associated with decreased antioxidant enzyme activity, enhanced oxidative marker, and changes in the expression of mitochondrial genes in comparison with the control rats. Co-treatment with VitD ameliorated all these changes. In conclusion, VitD could protect the heart against D-GAL-induced aging via enhancing antioxidant effects, and the expression of mitochondrial genes.

Mycn ameliorates cardiac hypertrophy-induced heart failure in mice by mediating the USP2/JUP/Akt/ß-catenin cascade.

BACKGROUND: Pathological cardiac hypertrophy is associated with cardiac dysfunction and is a key risk factor for heart failure and even sudden death. This study investigates the function of Mycn in cardiac hypertrophy and explores the interacting molecules. METHODS: A mouse model of cardiac hypertrophy was induced by isoproterenol (ISO). The cardiac dysfunction was assessed by the heart weight-to-body weight ratio (HW/BW), echocardiography assessment, pathological staining, biomarker detection, and cell apoptosis. Transcriptome alteration in cardiac hypertrophy was analyzed by bioinformatics analysis. Gain- or loss-of-function studies of MYCN proto-oncogene (Mycn), ubiquitin specific peptidase 2 (USP2), and junction plakoglobin (JUP) were performed. The biological functions of Mycn were further examined in ISO-treated cardiomyocytes. The molecular interactions were verified by luciferase assay or immunoprecipitation assays. RESULTS: Mycn was poorly expressed in ISO-treated mice, and its upregulation reduced HW/BW, cell surface area, oxidative stress, and inflammation while improving cardiac function of mice. It also reduced apoptosis of cardiomyocytes in mice and those in vitro induced by ISO. Mycn bound to the USP2 promoter to activate its transcription. USP2 overexpression exerted similar myocardial protective functions. It stabilized JUP protein by deubiquitination modification, which blocked the Akt/ß-catenin pathway. Knockdown of JUP restored phosphorylation of Akt and ß-catenin protein level, which negated the protective effects of USP2. CONCLUSION: This study demonstrates that Mycn activates USP2 transcription, which mediates ubiquitination and protein stabilization of JUP, thus inactivating the Akt/ß-catenin axis and alleviating cardiac hypertrophy-induced heart failure.

Low-Chloride Diet Prevents the Development of Arterial Hypertension and Protects Kidney Function in Angiotensin II-Infused Mice.

INTRODUCTION: A comprehensive pathophysiological mechanism to explain the relationship between high-salt intake and hypertension remains undefined. Evidence suggests that chloride, as the accompanying anion of sodium in dietary salt, is necessary to develop hypertension. We evaluated whether reducing dietary Cl- while keeping a standard Na+ intake modified blood pressure, cardiac hypertrophy, renal function, and vascular contractility after angiotensin II (AngII) infusion. METHODS: C56BL/6J mice fed with standard Cl- diet or a low-Cl- diet (equimolar substitution of Cl- by a mixture of Na+ salts, both diets with standard Na+ content) received AngII (infusion of 1.5 mg/kg/day) or vehicle for 14 days. We measured systolic blood pressure (SBP), glomerular filtration rate (GFR), natriuretic response to acute saline load, and contractility of aortic rings from mice infused with vehicle and AngII, in standard and low-Cl- diet. RESULTS: The mice fed the standard diet presented increased SBP and cardiac hypertrophy after AngII infusion. In contrast, low-Cl- diet prevented the increase of SBP and cardiac hypertrophy. AngII-infused mice fed a standard diet presented hampered natriuretic response to saline load, meanwhile the low-Cl- diet preserved natriuretic response in AngII-infused mice, without change in GFR. Aortic rings from mice fed with standard diet or low-Cl- diet and infused with AngII presented a similar contractile response. CONCLUSION: We conclude that the reduction in dietary Cl- as the accompanying anion of sodium in salt is protective from AngII pro-hypertensive actions due to a beneficial effect on kidney function and preserved natriuresis.

Ovarian Tumor Domain-Containing 7B Attenuates Pathological Cardiac Hypertrophy by Inhibiting Ubiquitination and Degradation of Krüppel-Like Factor 4.

BACKGROUND: Cardiac hypertrophy (CH) is a well-established risk factor for many cardiovascular diseases and a primary cause of mortality and morbidity among older adults. Currently, no pharmacological interventions have been specifically tailored to treat CH. OTUD7B (ovarian tumor domain-containing 7B) is a member of the ovarian tumor-related protease (OTU) family that regulates many important cell signaling pathways. However, the role of OTUD7B in the development of CH is unclear. Therefore, we investigated the role of OTUD7B in CH. METHODS AND RESULTS: OTUD7B knockout mice were used to assay the role of OTUD7B in CH after transverse aortic coarctation surgery. We further assayed the specific functions of OTUD7B in isolated neonatal rat cardiomyocytes. We found that OTUD7B expression decreased in hypertrophic mice hearts and phenylephrine-stimulated neonatal rat cardiomyocytes. Furthermore, OTUD7B deficiency exacerbated transverse aortic coarctation surgery-induced myocardial hypertrophy, abnormal cardiac function, and fibrosis. In cardiac myocytes, OTUD7B knockdown promoted phenylephrine stimulation-induced myocardial hypertrophy, whereas OTUD7B overexpression had the opposite effect. An immunoprecipitation-mass spectrometry analysis showed that OTUD7B directly binds to KLF4 (Krüppel-like factor 4). Additional molecular experiments showed that OTUD7B impedes KLF4 degradation by inhibiting lysine residue at 48 site-linked ubiquitination and suppressing myocardial hypertrophy by activating the serine/threonine kinase pathway. CONCLUSIONS: These results demonstrate that the OTUD7B-KLF4 axis is a novel molecular target for CH treatment.