Thymoquinone ameliorates pressure overload‐induced cardiac hypertrophy by activating the AMPK signalling pathway

Prolonged pathological myocardial hypertrophy leads to end‐stage heart failure. Thymoquinone (TQ), a bioactive component extracted from Nigella sativa seeds, is extensively used in ethnomedicine to treat a broad spectrum of disorders. However, it remains unclear whether TQ protects the heart from pathological hypertrophy. This study was conducted to examine the potential utility of TQ for treatment of pathological cardiac hypertrophy and if so, to elucidate the underlying mechanisms. Male C57BL/6J mice underwent either transverse aortic constriction (TAC) or sham operation, followed by TQ treatment for six consecutive weeks. In vitro experiments consisted of neonatal rat cardiomyocytes (NRCMs) that were exposed to phenylephrine (PE) stimulation to induce cardiomyocyte hypertrophy. In this study, we observed that systemic administration of TQ preserved cardiac contractile function, and alleviated cardiac hypertrophy, fibrosis and oxidative stress in TAC‐challenged mice. The in vitro experiments showed that TQ treatment attenuated the PE‐induced hypertrophic response in NRCMs. Mechanistical experiments showed that supplementation of TQ induced reactivation of the AMP‐activated protein kinase (AMPK) with concomitant inhibition of ERK 1/2, p38 and JNK1/2 MAPK cascades. Furthermore, we demonstrated that compound C, an AMPK inhibitor, abolished the protective effects of TQ in in vivo and in vitro experiments. Altogether, our study disclosed that TQ provides protection against myocardial hypertrophy in an AMPK‐dependent manner and identified it as a promising agent for the treatment of myocardial hypertrophy.     

Propofol depresses angiotensin II-induced cardiomyocyte hypertrophy in vitro

Cardiomyocyte hypertrophy is formed in response to pressure or volume overload, injury, or neurohormonal activation. The most important vascular hormone that contributes to the development of hypertrophy is angiotensin II (Ang II). Accumulating studies have suggested that reactive oxygen species (ROS) may play an important role in cardiac hypertrophy. Propofol is a general anesthetic that possesses antioxidant action. We therefore examined whether propofol inhibited Ang II-induced cardiomyocyte hypertrophy. Our results showed that both ROS formation and hypertrophic responses induced by Ang II in cardiomyocytes were partially blocked by propofol. Further studies showed that propofol inhibited the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and mitogen-activated protein kinase/ERK kinase 1/2 (MEK1/2) induced by Ang II via a decrease in ROS production. In addition, propofol also markedly attenuated Ang II-stimulated nuclear factor-kappaB (NF-kappaB) activation via a decrease in ROS production. In conclusion, propofol prevents cardiomyocyte hypertrophy by interfering with the generation of ROS and involves the inhibition of the MEK/ERK signaling transduction pathway and NF-kappaB activation.     

Early NADPH oxidase-2 activation is crucial in phenylephrine-induced hypertrophy of H9c2 cells

Reactive oxygen species (ROS) produced by different NADPH oxidases (NOX) play a role in cardiomyocyte hypertrophy induced by different stimuli, such as angiotensin II and pressure overload. However, the role of the specific NOX isoforms in phenylephrine (PE)-induced cardiomyocyte hypertrophy is unknown. Therefore we aimed to determine the involvement of the NOX isoforms NOX1, NOX2 and NOX4 in PE-induced cardiomyocyte hypertrophy. Hereto rat neonatal cardiomyoblasts (H9c2 cells) were incubated with 100 μM PE to induce hypertrophy after 24 and 48 h as determined via cell and nuclear size measurements using digital imaging microscopy, electron microscopy and an automated cell counter. Digital-imaging microscopy further revealed that in contrast to NOX1 and NOX4, NOX2 expression increased significantly up to 4 h after PE stimulation, coinciding and co-localizing with ROS production in the cytoplasm as well as the nucleus. Furthermore, inhibition of NOX-mediated ROS production with apocynin, diphenylene iodonium (DPI) or NOX2 docking sequence (Nox2ds)-tat peptide during these first 4 h of PE stimulation significantly inhibited PE-induced hypertrophy of H9c2 cells, both after 24 and 48 h of PE stimulation. These data show that early NOX2-mediated ROS production is crucial in PE-induced hypertrophy of H9c2 cells.     

Scoparone alleviates Ang II-induced pathological myocardial hypertrophy in mice by inhibiting oxidative stress

Long-term poorly controlled myocardial hypertrophy often leads to heart failure and sudden death. Activation of ras-related C3 botulinum toxin substrate 1 (RAC1) by angiotensin II (Ang II) plays a pivotal role in myocardial hypertrophy. Previous studies have demonstrated that scoparone (SCO) has beneficial effects on hypertension and extracellular matrix remodelling. However, the function of SCO on Ang II-mediated myocardial hypertrophy remains unknown. In our study, a mouse model of myocardial hypertrophy was established by Ang II infusion (2 mg/kg/day) for 4 weeks, and SCO (60 mg/kg bodyweight) was administered by gavage daily. In vitro experiments were also performed. Our results showed that SCO could alleviate Ang II infusion-induced cardiac hypertrophy and fibrosis in mice. In vitro, SCO treatment blocks Ang II-induced cardiomyocyte hypertrophy, cardiac fibroblast collagen synthesis and differentiation to myofibroblasts. Meanwhile, we found that SCO treatment blocked Ang II-induced oxidative stress in cardiomyocytes and cardiac fibroblasts by inhibiting RAC1-GTP and total RAC1 in vivo and in vitro. Furthermore, reactive oxygen species (ROS) burst by overexpression of RAC1 completely abolished SCO-mediated protection in cardiomyocytes and cardiac fibroblasts in vitro. In conclusion, SCO, an antioxidant, may attenuate Ang II-induced myocardial hypertrophy by suppressing of RAC1 mediated oxidative stress.     

Allicin protects against cardiac hypertrophy and fibrosis via attenuating reactive oxygen species-dependent signaling pathways

Increased oxidative stress has been associated with the pathogenesis of chronic cardiac hypertrophy and heart failure. Since allicin suppresses oxidative stress in vitro and in vivo, we hypothesized that allicin would inhibit cardiac hypertrophy through blocking oxidative stress-dependent signaling. We examined this hypothesis using primary cultured cardiac myocytes and fibroblasts and one well-established animal model of cardiac hypertrophy. Our results showed that allicin markedly inhibited hypertrophic responses induced by Ang II or pressure overload. The increased reactive oxygen species (ROS) generation and NADPH oxidase activity were significantly suppressed by allicin. Our further investigation revealed this inhibitory effect on cardiac hypertrophy was mediated by blocking the activation of ROS-dependent ERK1/2, JNK1/2 and AKT signaling pathways. Additional experiments demonstrated allicin abrogated inflammation and fibrosis by blocking the activation of nuclear factor-κB and Smad 2/3 signaling, respectively. The combination of these effects resulted in preserved cardiac function in response to cardiac stimuli. Consequently, these findings indicated that allicin protected cardiac function and prevented the development of cardiac hypertrophy through ROS-dependent mechanism involving multiple intracellular signaling.     

Critical role of X-box binding protein 1 in NADPH oxidase 4-triggered cardiac hypertrophy is mediated by receptor interacting protein kinase 1

NADPH oxidase 4 (NOX4) and the NOX4-related redox signaling are implicated in cardiac hypertrophy. NOX4 is interrelated with endoplasmic reticulum stress (ERS). Spliced X-box binding protein 1 (Xbp1s) is a key mediator of ERS while its role in cardiac hypertrophy is still poorly understood. Recently, receptor interacting protein kinase 1(RIPK1) has been increasingly reported to be associated with ERS. Therefore, we aimed to test the hypothesis that Xbp1s mediates NOX4-triggered cardiac hypertrophy via RIPK1 signaling. In the heart tissue of transverse aortic constriction (TAC) rats and in primary cultured neonatal cardiomyocytes(NCMs) treated with angiotensinII(AngII) or isoproterenol (ISO), NOX4 expression and reactive oxygen species (ROS) generation, and expression of Xbp1s as well as RIPK1-related phosphorylation of P65 subunit of NF-κB were elevated. Gene silencing of NOX4 by specific small interfering RNA (siRNA) significantly blocked the upregulation of NOX4, generation of ROS, splicing of Xbp1 and activation of the RIPK1-related NF-κB signaling, meanwhile attenuated cardiomyocyte hypertrophy. In addition, ROS scavenger (N-acetyl-L-cysteine, NAC) and NOX4 inhibitor GKT137831 reduced ROS generation and alleviated activation of Xbp1 and RIPK1-related NF-κB signaling. Furthermore, splicing of Xbp1 was responsible for the increase in RIPK1 expression in AngII or ISO-treated NCMs. Upregulated RIPK1 in turn activates NF-κB signaling in a kinase activity-independent manner. These findings suggest that Xbp1s plays an important role in NOX4-triggered cardiomyocyte hypertrophy via activating its downstream effector RIPK1, which may prove significant for the development of future therapeutic strategies.     

Cardiac‐specific Mst1 deficiency inhibits ROS‐mediated JNK signalling to alleviate Ang II‐induced cardiomyocyte apoptosis

Apoptosis is associated with various myocardial diseases. Angiotensin II (Ang II) plays a central role in the pathogenesis of RAAS‐triggered cardiac apoptosis. Our previous studies showed that mammalian Ste20‐like kinase 1 (Mst1) aggravates cardiac dysfunction in cardiomyocyte under pathological conditions, but its role in Ang II‐mediated cardiomyocyte apoptosis is not known. We addressed this in the present study by investigating whether cardiac‐specific Mst1 knockout can alleviate Ang II‐induced cardiomyocyte apoptosis along with the underlying mechanisms. In vitro and in vivo experiments showed that Ang II increased intracellular reactive oxygen species (ROS) production and cardiomyocyte apoptosis; these were reversed by administration of the ROS scavenger N‐acetylcysteine and by Mst1 deficiency, which suppressed c‐Jun N‐terminal kinase (JNK) phosphorylation and downstream signaling. Interestingly, Mst1 knockout failed to alleviate Ang II‐induced phosphorylation of extracellular signal‐regulated kinase 1/2, and inactivated apoptosis signal‐regulating kinase1 (ASK1) by promoting its association with thioredoxin (Trx), which reversed the Ang II‐induced activation of the ASK1–JNK pathway and suppressed Ang II‐induced cardiomyocyte apoptosis. Thus, cardiac‐specific Mst1 knockout inhibits ROS‐mediated JNK signalling to block Ang II‐induced cardiomyocyte apoptosis, suggesting Mst1 as a potential therapeutic target for treatment of RAAS‐activated heart failure.     

Multiple signaling pathways coordinately mediate reactive oxygen species dependent cardiomyocyte hypertrophy

The heart responds to an increased demand arising due to physiological stimuli or pathological insults by hypertrophy of myocytes. Reactive oxygen species (ROS) have recently been identified as the molecular intermediates in the translation of mechanical stimuli to cellular response. Different signal transduction pathways have been implicated with cardiac hypertrophy, prominent among them being, mitogen-activated protein kinase (MAPK), protein kinase C (PKC) and calcineurin. It remains unclear whether the ROS induced hypertrophy is mediated through one or more of these pathways. This study was taken up with the objective to affirm the role of ROS in the induction of cardiomyocyte hypertrophy and examine the contribution of specific pathways in the mediation of the hypertrophic response. The cellular response to enzyme-generated reactive oxygen species was examined in cultured cells from newborn rat heart. Pathway specific inhibitors were used to identify the role of each pathway in the mediation of cellular hypertrophy. Cellular hypertrophy in response to hypoxanthine-xanthine oxidase was prevented by inhibition of any one of the pathways; leading to the inference that oxidative stress induced hypertrophy is mediated by coordinative regulation of the three major pathways.     

HMG-CoA reductase inhibitor fluvastatin prevents angiotensin II-induced cardiac hypertrophy via Rho kinase and inhibition of cyclin D1

HMG-CoA reductase inhibitors, so called statins, decrease cardiac events. Previous studies have shown that HMG-CoA reductase inhibitors inhibit cardiomyocyte hypertrophy in vitro and in vivo by blocking Rho isoprenylation. We have shown that the G1 cell cycle regulatory proteins cyclin D1 and Cdk4 play important roles in cardiomyocyte hypertrophy. However, the relation between Rho and cyclin D1 in cardiomyocyte is unknown. To investigate whether HMG-CoA reductase inhibitors prevent cardiac hypertrophy through attenuation of Rho and cyclin D1, we studied the effect of fluvastatin on angiotensin II-induced cardiomyocyte hypertrophy in vitro and in vivo. Angiotensin II increased the cell surface area and [(3)H]leucine uptake of cultured neonatal rat cardiomyocytes and these changes were suppressed by fluvastatin treatment. Angiotensin II also induced activation of Rho kinase and increased cyclin D1, both of which were also significantly suppressed by fluvastatin. Specific Rho kinase inhibitor, Y-27632 inhibited angiotensin II-induced cardiomyocyte hypertrophy and increased cyclin D1. Overexpression of cyclin D1 by adenoviral gene transfer induced cardiomyocyte hypertrophy, as evidenced by increased cell size and increased protein synthesis; this hypertrophy was not diminished by concomitant treatment with fluvastatin. Infusion of angiotensin II to Wistar rats for 2 weeks induced hypertrophic changes in cardiomyocytes, and this hypertrophy was prevented by oral fluvastatin treatment. These results show that an HMG-CoA reductase inhibitor, fluvastatin, prevents angiotensin II-induced cardiomyocyte hypertrophy in part through inhibition of cyclin D1, which is linked to Rho kinase. This novel mechanism discovered for fluvastatin could be revealed how HMG-CoA reductase inhibitors are preventing cardiac hypertrophy.     

Exogenous hydrogen sulfide prevents cardiomyocyte apoptosis from cardiac hypertrophy induced by isoproterenol

Oxidative stress is a crucial factor inducing cardiomyocyte apoptosis due to cardiac hypertrophy. Additional evidence has revealed that H₂S plays an antioxidant role and is cytoprotective. Hence, we aimed to elucidate whether H₂S prevents cardiomyocyte apoptosis due to cardiac hypertrophy via its antioxidant function. The cardiac hypertrophy model was obtained by injecting a high dose of isoproterenol (ISO) subcutaneously, and the hemodynamic parameters were measured in groups that received either ISO or ISO with the treatment of NaHS. TUNEL (terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling) and EM (electron microscopy) experiments were performed to determine the occurrence of apoptosis in heart tissues. The expression of caspase-3 protein in the cytoplasm and NADPH oxidase 4 (NOX4), and cytochrome c (cyt c) proteins in the mitochondria were analyzed using Western blotting. In contrast, to determine whether ISO-induced apoptosis in the cultured cardiomyocytes may be related to oxidative stress, JC-1 and MitoSOX assays were performed to detect the mitochondrial membrane potential and reactive oxygen species (ROS) production in the mitochondria. Exogenous H₂S was found to ameliorate cardiac function. The histological observations obtained from TUNEL and EM demonstrated that treatment with NaHS inhibited the occurrence of cardiac apoptosis and improved cardiac structure. Moreover, H₂S reduced the expression of the cleaved caspase-3, NOX4 and the leakage of cyt c from the mitochondria to the cytoplasm. We also observed that exogenous H₂S could maintain the mitochondrial membrane potential and reduce ROS production in the mitochondria. Therefore, H₂S reduces oxidative stress due to cardiac hypertrophy through the cardiac mitochondrial pathway.     

Activation of catalase by apelin prevents oxidative stress-linked cardiac hypertrophy

Adipose tissue secretes a variety of bioactive factors, which can regulate cardiomyocyte hypertrophy via reactive oxygen species (ROS). In the present study we investigated whether apelin affects ROS-dependent cardiac hypertrophy. In cardiomyocytes apelin inhibited the hypertrophic response to 5-HT and oxidative stress induced by 5-HT- or H₂O₂ in a dose-dependent manner. These effects were concomitant to the increase in mRNA expression and activity of catalase. Chronic treatment of mice with apelin attenuated pressure-overload-induced left ventricular hypertrophy. The prevention of hypertrophy by apelin was associated with increased myocardial catalase activity and decreased plasma lipid hydroperoxide, as an index of oxidative stress. These results show that apelin behaves as a catalase activator and prevents cardiac ROS-dependent hypertrophy.     

Zerumbone prevents pressure overload-induced left ventricular systolic dysfunction by inhibiting cardiac hypertrophy and fibrosis

BackgroundCardiac hypertrophy and fibrosis are hallmarks of cardiac remodeling and are involved functionally in the development of heart failure (HF). However, it is unknown whether Zerumbone (Zer) prevents left ventricular (LV) systolic dysfunction by inhibiting cardiac hypertrophy and fibrosis.PurposeThis study investigated the effect of Zer on cardiac hypertrophy and fibrosis in vitro and in vivo.Study Design/methodsIn primary cultured cardiac cells from neonatal rats, the effect of Zer on phenylephrine (PE)-induced hypertrophic responses and transforming growth factor beta (TGF-β)-induced fibrotic responses was observed. To determine whether Zer prevents the development of pressure overload-induced HF in vivo, a transverse aortic constriction (TAC) mouse model was utilized. Cardiac function was evaluated by echocardiography. The changes of cardiomyocyte surface area were observed using immunofluorescence staining and histological analysis (HE and WGA staining). Collagen synthesis and fibrosis formation were measured by scintillation counter and picrosirius staining, respectively. The total mRNA levels of genes associated with hypertrophy (ANF and BNP) and fibrosis (Postn and α-SMA) were measured by qRT-PCR. The protein expressions (Akt and α-SMA) were assessed by western blotting.ResultsZer significantly suppressed PE-induced increase in cell size, mRNA levels of ANF and BNP, and Akt phosphorylation in cardiomyocytes. The TGF-β-induced increase in proline incorporation, mRNA levels of Postn and α-SMA, and protein expression of α-SMA were decreased by Zer in cultured cardiac fibroblasts. In the TAC male C57BL/6 mice, echocardiography results demonstrated that Zer improved cardiac function by increasing LV fractional shortening and reducing LV wall thickness compared with the vehicle group. ZER significantly reduced the level of phosphorylated Akt both in cultured cardiomyocytes treated with PE and in the hearts of TAC. Finally, Zer inhibited the pressure overload-induced cardiac hypertrophy and cardiac fibrosis.ConclusionZer ameliorates pressure overload-induced LV dysfunction, at least in part by suppressing both cardiac hypertrophy and fibrosis.     

Crocetin protects against cardiac hypertrophy by blocking MEK-ERK1/2 signalling pathway

Oxidative stress plays a critical role in the progression of pathological cardiac hypertrophy and heart failure. Because crocetin represses oxidative stress in vitro and in vivo , we have suggested that crocetin would repress cardiac hypertrophy by targeting oxidative stress-dependent signalling. We tested this hypothesis using primary cultured cardiac myocytes and fibroblasts and one well-established animal model of cardiac hypertrophy. The results showed that crocetin (1–10 μM) dose-dependently blocked cardiac hypertrophy induced by angiogensin II (Ang II; 1 μM) in vitro . Our data further revealed that crocetin (50 mg/kg/day) both prevented and reversed cardiac hypertrophy induced by aortic banding (AB), as assessed by heart weight/body weight and lung weight/body weight ratios, echocardio-graphic parameters and gene expression of hypertrophic markers. The inhibitory effect of crocetin on cardiac hypertrophy is mediated by blocking the reactive oxygen species (ROS)-dependent mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase-1/2 (MEK/ERK1/2) pathway and GATA binding protein 4 (GATA-4) activation. Further investigation demonstrated that crocetin inhibited inflammation by blocking nuclear factor kappa B (NF-κB) signalling and attenuated fibrosis and collagen synthesis by abrogating MEK-ERK1/2 signalling. Overall, our results indicate that crocetin, which is a potentially safe and inexpensive therapy for clinical use, has protective potential in targeting cardiac hypertrophy and fibrosis by suppression of ROS-dependent signalling pathways.     

Tom70 serves as a molecular switch to determine pathological cardiac hypertrophy

Pathological cardiac hypertrophy is an inevitable forerunner of heart failure. Regardless of the etiology of cardiac hypertrophy, cardiomyocyte mitochondrial alterations are always observed in this context. The translocases of mitochondrial outer membrane (Tom) complex governs the import of mitochondrial precursor proteins to maintain mitochondrial function under pathophysiological conditions; however, its role in the development of pathological cardiac hypertrophy remains unclear. Here, we showed that Tom70 was downregulated in pathological hypertrophic hearts from humans and experimental animals. The reduction in Tom70 expression produced distinct pathological cardiomyocyte hypertrophy both in vivo and in vitro. The defective mitochondrial import of Tom70-targeted optic atrophy-1 triggered intracellular oxidative stress, which led to a pathological cellular response. Importantly, increased Tom70 levels provided cardiomyocytes with full resistance to diverse pro-hypertrophic insults. Together, these results reveal that Tom70 acts as a molecular switch that orchestrates hypertrophic stresses and mitochondrial responses to determine pathological cardiac hypertrophy.     

活性氧介导内皮素-1诱导的培养新生大鼠心肌细胞肥大

实验在原代培养的新生大鼠心肌细胞中进行,检测内皮素-1(endothelin-1,ET-1)及其他药物对心肌细胞活性氧(reactiveoxygen species,ROS)产生和心肌细胞肥大的作用,以探讨ROS在ET-1诱导的心肌细胞肥大信号通路中的作用及ROS与蛋白激酶C(protein kinase C,PKC)活化的关系。细胞内ROS水平用ROS敏感的荧光探针2,7-dichlorofluorescin dictate(DCF-DA)反映,心肌细胞肥大通过细胞内RNA含量、细胞内蛋白质含量、细胞表面积大小来确定。实验结果如下:单独使用ET-1后,心肌细胞内反应ROS含量的DCF-DA荧光值比对照组增加77%,反应心肌肥大的PI荧光值、细胞内蛋白质含量、细胞表面积也分别比对照组增加128%、87%和151%。ET-1合用内皮素受体A亚型(ET_A)受体拮抗剂ABT-627、PKC抑制剂CC或过氧化氢酶后,DCF-DA的增加分别减弱62%、60%和51%,同时心肌细胞肥大也被抑制,单独使用PKC激动剂佛波醇脂(PMA)也能使DCF-DA的产生比对照组增加74%。因此,在ET-1诱导心肌细胞肥大的过程中,ET-1能够使心肌细胞产生ROS和诱导ROS依赖的心肌细胞肥大,这一作用依赖于ET_A受体的激活和PKC的活化,·ROS在ET-1诱导心肌细胞肥大中起信号传递的作用。     

β-Catenin/TCF/LEF1 can directly regulate phenylephrine-induced cell hypertrophy and Anf transcription in cardiomyocytes

β-Catenin/TCF/LEF1 signaling is implicated in cardiac hypertrophy. We demonstrate that knockdown of β-catenin attenuates phenylephrine (PE)-induced cardiomyocyte hypertrophy and the up-regulation of the fetal gene Anf. We explore the mechanism through which β-catenin regulates Anf expression and find a consensus binding sequence on the Anf promoter for TCF/LEF1 family members. LEF1 binds directly to the Anf promoter via this sequence, which shows functional significance, and PE stimulation enhances recruitment of β-catenin onto the Anf promoter. Thus, we document a direct positive role of β-catenin on PE-induced cardiomyocyte hypertrophy and identify a new target gene for β-catenin/TCF/LEF1.     

Targeting the upregulation of reactive oxygen species subsequent to hyperglycemia prevents type 1 diabetic cardiomyopathy in mice

Cardiac oxidative stress is an early event associated with diabetic cardiomyopathy, triggered by hyperglycemia. We tested the hypothesis that targeting left-ventricular (LV) reactive oxygen species (ROS) upregulation subsequent to hyperglycemia attenuates type 1 diabetes-induced LV remodeling and dysfunction, accompanied by attenuated proinflammatory markers and cardiomyocyte apoptosis. Male 6-week-old mice received either streptozotocin (55 mg/kg/day for 5 days), to induce type 1 diabetes, or citrate buffer vehicle. After 4 weeks of hyperglycemia, the mice were allocated to coenzyme Q₁₀ supplementation (10 mg/kg/day), treatment with the angiotensin-converting-enzyme inhibitor (ACE-I) ramipril (3 mg/kg/day), treatment with olive oil vehicle, or no treatment for 8 weeks. Type 1 diabetes upregulated LV NADPH oxidase (Nox2, p22^phox, p47^phox and superoxide production), LV uncoupling protein UCP3 expression, and both LV and systemic oxidative stress (LV 3-nitrotyrosine and plasma lipid peroxidation). All of these were significantly attenuated by coenzyme Q₁₀. Coenzyme Q₁₀ substantially limited type 1 diabetes-induced impairments in LV diastolic function (E:A ratio and deceleration time by echocardiography, LV end-diastolic pressure, and LV −dP/dt by micromanometry), LV remodeling (cardiomyocyte hypertrophy, cardiac fibrosis, apoptosis), and LV expression of proinflammatory mediators (tumor necrosis factor-α, with a similar trend for interleukin IL-1β). Coenzyme Q_10's actions were independent of glycemic control, body mass, and blood pressure. Coenzyme Q₁₀ compared favorably to improvements observed with ramipril. In summary, these data suggest that coenzyme Q₁₀ effectively targets LV ROS upregulation to limit type 1 diabetic cardiomyopathy. Coenzyme Q₁₀ supplementation may thus represent an effective alternative to ACE-Is for the treatment of cardiac complications in type 1 diabetic patients.     

GPR39 promotes cardiac hypertrophy by regulating the AMPK–mTOR pathway and protein synthesis

Hypertrophic growth of the cardiomyocytes is one of the core mechanisms underlying cardiac hypertrophy. However, the mechanism underlying cardiac hypertrophy remains not fully understood. Here we provided evidence that G protein-coupled receptor 39 (GPR39) promotes cardiac hypertrophy via inhibiting AMP-activated protein kinase (AMPK) signaling. GRP39 expression is overexpressed in hypertrophic hearts of humans and transverse aortic constriction (TAC)-induced cardiac hypertrophy in mice. In neonatal cardiomyocytes, adenovirus-mediated overexpression of GPR39 promoted angiotensin II-induced cardiac hypertrophy, while GPR39 knockdown repressed hypertrophic response. Adeno-associated virus 9-mediated knockdown of GPR39 suppressed TAC-induced decline in fraction shortening and ejection fraction, increase in heart weight and cardiomyocyte size, as well as overexpression of hypertrophic fetal genes. A mechanism study demonstrated that GPR39 repressed the activation of AMPK to activate the mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase β-1 (S6K1), subsequently promoted de novo protein synthesis. Inhibition of mTOR with rapamycin blocked the effects of GPR39 overexpression on protein synthesis and repressed cardiac hypertrophy. Collectively, our findings demonstrated that GPR39 promoted cardiac hypertrophy via regulating the AMPK–mTOR–S6K1 signaling pathway, and GRP39 can be targeted for the treatment of cardiac hypertrophy.