Myocardial Hypertrophy In Mice Research Articles

Effect and mechanism of gomisin D on the isoproterenol induced myocardial injury in H9C2 cells and mice

We established myocardial injury models in vivo and in vitro to investigate the cardioprotective effect of gomisin D obtained from Schisandra chinensis. Gomisin D significantly inhibited isoproterenol-induced apoptosis and hypertrophy in H9C2 cells. Gomisin D decreased serum BNP, ANP, CK-MB, cTn-T levels and histopathological alterations, and inhibited myocardial hypertrophy in mice. In mechanisms research, gomisin D reversed ISO-induced accumulation of intracellular ROS and Ca2+. Gomisin D further improved mitochondrial energy metabolism disorders by regulating the TCA cycle. These results demonstrated that gomisin D had a significant effect on isoproterenol-induced myocardial injury by inhibiting oxidative stress, calcium overload and improving mitochondrial energy metabolism.

Zonisamide attenuates pressure overload-induced myocardial hypertrophy in mice through proteasome inhibition.

Myocardial hypertrophy is a pathological thickening of the myocardium which ultimately results in heart failure. We previously reported that zonisamide, an antiepileptic drug, attenuated pressure overload-caused myocardial hypertrophy and diabetic cardiomyopathy in murine models. In addition, we have found that the inhibition of proteasome activates glycogen synthesis kinase 3 (GSK-3) thus alleviates myocardial hypertrophy, which is an important anti-hypertrophic strategy. In this study, we investigated whether zonisamide prevented pressure overload-caused myocardial hypertrophy through suppressing proteasome. Pressureoverload-caused myocardial hypertrophy was induced in mice by trans-aortic constriction (TAC) surgery. Two days after the surgery, the mice were administered zonisamide (10, 20, 40 mg·kg-1·d-1, i.g.) for four weeks. We showed that zonisamide administration significantly mitigated impaired cardiac function. Furthermore, zonisamide administration significantly inhibited proteasome activity as well as the expression levels of proteasome subunit beta types (PSMB) of the 20 S proteasome (PSMB1, PSMB2 and PSMB5) and proteasome-regulated particles (RPT) of the 19 S proteasome (RPT1, RPT4) in heart tissues of TAC mice. In primary neonatal rat cardiomyocytes (NRCMs), zonisamide (0.3 μM) prevented myocardial hypertrophy triggered by angiotensin II (Ang II), and significantly inhibited proteasome activity, proteasome subunits and proteasome-regulated particles. In Ang II-treated NRCMs, we found that 18α-glycyrrhetinic acid (18α-GA, 2 mg/ml), a proteasome inducer, eliminated the protective effects of zonisamide against myocardial hypertrophy and proteasome. Moreover, zonisamide treatment activated GSK-3 through inhibiting the phosphorylated AKT (protein kinase B, PKB) and phosphorylated liver kinase B1/AMP-activated protein kinase (LKB1/AMPKα), the upstream of GSK-3. Zonisamide treatment also inhibited GSK-3's downstreamsignaling proteins, including extracellular signal-regulated kinase (ERK) and GATA binding protein 4 (GATA4), both being the hypertrophic factors. Collectively, this study highlights the potential of zonisamide as a new therapeutic agent for myocardial hypertrophy, as it shows potent anti-hypertrophic potential through the suppression of proteasome.

Dapagliflozin attenuates myocardial hypertrophy via activating the SIRT1/HIF-1α signaling pathway

As a sodium-glucose transporter 2 inhibitor (SGLT2i), the cardioprotective benefits of Dapagliflozin (DAPA) are now widely appreciated. However, the underlying mechanism of DAPA on angiotensin II (Ang II)-induced myocardial hypertrophy has never been evaluated. In this study, we not only investigated the effects of DAPA on Ang II-induced myocardial hypertrophy, but explored its underlying mechanisms. Mice were injected with Ang II (500 ng /kg/min) or saline solution as control, followed by intragastric administration DAPA (1.5 mg/kg/day) or saline for four weeks. DAPA treatment alleviated the condition of decrease in left ventricular ejection fraction (LVEF) and fractional shortening (LVFS) caused by Ang II. In addition, DAPA treatment significantly alleviated Ang II-induced elevation of the ratio of heart weight to tibia length, as well as cardiac injury and hypertrophy. In mice stimulated with Ang II, the degree of myocardial fibrosis and upregulation of the markers of cardiac hypertrophy (atrial natriuretic peptide, ANP and B-type natriuretic peptide, BNP) were attenuated by DAPA. What’s more, DAPA partially reversed the Ang II-induced upregulation of HIF-1α and the decrease in levels of SIRT1. Taken together, activating the SIRT1/HIF-1α signaling pathway was found to confer a protective effect against experimental myocardial hypertrophy in mice induced by Ang II, demonstrating its potential as an effective therapeutic target for pathological cardiac hypertrophy.

CDC-like kinase 4 deficiency contributes to pathological cardiac hypertrophy by modulating NEXN phosphorylation

Kinase-catalyzed phosphorylation plays a crucial role in pathological cardiac hypertrophy. Here, we show that CDC-like kinase 4 (CLK4) is a critical regulator of cardiomyocyte hypertrophy and heart failure. Knockdown of Clk4 leads to pathological cardiomyocyte hypertrophy, while overexpression of Clk4 confers resistance to phenylephrine-induced cardiomyocyte hypertrophy. Cardiac-specific Clk4-knockout mice manifest pathological myocardial hypertrophy with progressive left ventricular systolic dysfunction and heart dilation. Further investigation identifies nexilin (NEXN) as the direct substrate of CLK4, and overexpression of a phosphorylation-mimic mutant of NEXN is sufficient to reverse the hypertrophic growth of cardiomyocytes induced by Clk4 knockdown. Importantly, restoring phosphorylation of NEXN ameliorates myocardial hypertrophy in mice with cardiac-specific Clk4 deletion. We conclude that CLK4 regulates cardiac function through phosphorylation of NEXN, and its deficiency may lead to pathological cardiac hypertrophy. CLK4 is a potential intervention target for the prevention and treatment of heart failure.

Polyphenol-assisted facile assembly of bioactive nanoparticles for targeted therapy of heart diseases

It remains a great challenge for targeted therapy of heart diseases. To achieve desirable heart targeting, we developed a polyphenol-assisted nanoprecipitation/self-assembly approach for facile engineering of functional nanoparticles. Three different materials were employed as representative carriers, while gallic acid, catechin, epigallocatechin gallate, and tannic acid (TA) served as typical polyphenols with varied numbers of phenolic hydroxyl groups. By optimizing different parameters, such as polyphenol types and the weight ratio of carrier materials and polyphenols, well-defined nanoparticles with excellent physicochemical properties can be easily prepared. Regardless of various carrier materials, TA-derived nanoparticles showed potent reactive oxygen species-scavenging activity, especially nanoparticles produced from a cyclodextrin-derived bioactive material (TPCD). By internalization into cardiomyocytes, TPCD/TA nanoparticles (defined as TPTN) effectively protected cells from hypoxic-ischemic injury. After intravenous injection, TPTN considerably accumulated in the injured heart in two murine models of ventricular fibrillation cardiac arrest in rats and myocardial hypertrophy in mice. Correspondingly, intravenously delivered TPTN afforded excellent therapeutic effects in both heart diseases. Preliminary experiments also revealed good safety of TPTN. These results substantiated that TPTN is a promising nanotherapy for targeted treatment of heart diseases, while polyphenol-assisted self-assembly is a facile but robust strategy to develop heart-targeting delivery systems.

[Contribution of sympathetic activation to antihypertrophic memory after regression of exercise-induced physiological myocardial hypertrophy in mice].

To investigate whether anti-hypertrophic memory exists after regression of exercise-induced physiological myocardial hypertrophy (PMH) and explore the contribution of sympathetic activation to hypertrophic memory formation. Seventy-two mice were randomized equally into 6 groups, including sedentary sham-operated group, exercise hypertrophic preconditioning (EHP) + sham operation group, bisoprolol (an adrenergic β1 receptor blocker) + EHP + sham operation group (biso+Exe+Sham group), sedentary group with transverse aortic constriction (TAC) (Sed+TAC group), EHP+ TAC group (Exe+TAC group), and bisoprolol+EHP+TAC group (biso+Exe+TAC group). The mice in the EHP groups were subjected to 3 weeks of swimming training, and in the bisoprolol groups, bisoprolol was administered by gavage once daily from two days before till the end of the training. One week after the training, TAC or sham surgery was performed. Echocardiography and hemodynamic measurements were performed to evaluate cardiac function of the mice, and the myocardial tissues were examined histologically to detect cardiac remodeling. Compared with the sedentary group, the mice receiving 3 weeks of swimming training had significantly increased heart weight to body weight ratio (HW/BW), HW to tibia length ratio (HW/TL), and the cross-sectional area of the cardiomyocytes (P < 0.05). One week after the training, exercise-induced PMH rapidly diminished and both HW/BW and HW/TL recovered the baseline levels. Treatment with bisoprolol obviously prevented the occurrence of PMH. Four weeks after TAC, the left ventricular posterior wall thickness, HW/BW, HW/TL, left ventricular end diastolic pressure and cross-sectional area of cardiomyocytes were all significantly lower (P < 0.05) while the left ejection fraction and maximal change rate of left ventricular pressure were significantly higher (P < 0.05) in Exe + TAC group than in Sed + TAC group. No significant difference was found in these parameters between biso + Exe + TAC group and Sed + TAC group. Anti-hypertrophic memory exists even after the regression of exercise-induced PMH, which may be attributed to the activation of sympathetic nervous system during exercise.

Comparative studies on regional variations in PM2.5 in the induction of myocardial hypertrophy in mice

Exposure to fine particulate matter (PM2.5) has been indicated to be related to an increased risk of cardiovascular diseases (CVDs) in sensitive people. However, the underlying mechanisms of PM2.5-induced CVDs are poorly understood. In the present study, PM2.5 samples were collected during winter from four cities (Taiyuan, Beijing, Hangzhou, and Guangzhou) in China. Ten-month-old C57BL/6 female mice were exposed to PM2.5 suspension at a dosage of 3 mg·kg−1 (b. w.) every other day for 4 weeks by oropharyngeal aspiration. PM2.5 from Taiyuan increased the blood pressure and the thicknesses of the left ventricular anterior and posterior walls, decreased the ratio of nucleus to cytoplasm in cardiomyocytes and reduced the systolic function of the heart in mice. Further investigation revealed that PM2.5 from Taiyuan induced lung inflammatory cytokines with up-regulated expressions of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). The mRNA expression levels of myocardial hypertrophy markers atrial natriuretic peptide and the β isoform of myosin heavy chain (ANP and β-MHC), matrix metalloproteinase 2 (MMP2), MMP9, and inflammatory cytokines TNF-α and IL-6 in the myocardium were significantly increased after exposure to PM2.5 of Taiyuan. Furthermore, PM2.5 from Taiyuan activated the IL-6/JAK2/STAT3/β-MHC signaling pathway in the myocardium. The correlation between the PM2.5 components and myocardial hypertrophy markers suggested that Zinc (Zn) and acenaphthene (AC) are related to the changes in ANP and β-MHC at the transcriptional level, respectively. The above results indicated that PM2.5 exposure induced myocardial hypertrophy in older mice, which might be related to the critical contributions of Zn and AC in PM2.5. The present study provides new insights into the mechanism of myocardial hypertrophy after PM2.5 exposure.

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.

I-κB Kinase-ε Deficiency Attenuates the Development of Angiotensin II-Induced Myocardial Hypertrophy in Mice.

I-κB kinase-ε (IKKε) is a member of the IKK complex and a proinflammatory regulator that is active in many diseases. Angiotensin II (Ang II) is a vasoconstricting peptide hormone, and Ang II-induced myocardial hypertrophy is a common cardiovascular disease that can result in heart failure. In this study, we sought to determine the role of IKKε in the development of Ang II-induced myocardial hypertrophy in mice. Wild-type (WT) and IKKε-knockout (IKKε-KO) mice were generated and infused with saline or Ang II for 8 weeks. We found that WT mouse hearts have increased IKKε expression after 8 weeks of Ang II infusion. Our results further indicated that IKKε-KO mice have attenuated myocardial hypertrophy and alleviated heart failure compared with WT mice. Additionally, Ang II-induced expression of proinflammatory and collagen factors was much lower in the IKKε-KO mice than in the WT mice. Apoptosis and pyroptosis were also ameliorated in IKKε-KO mice. Mechanistically, IKKε bound to extracellular signal-regulated kinase (ERK) and the mitogen-activated protein kinase p38, resulting in MAPK/ERK kinase (MEK) phosphorylation, and IKKε deficiency inhibited the phosphorylation of MEK-ERK1/2 and p38 in mouse heart tissues after 8 weeks of Ang II infusion. The findings of our study reveal that IKKε plays an important role in the development of Ang II-induced myocardial hypertrophy and may represent a potential therapeutic target for the management of myocardial hypertrophy.

Effect of β-casomorphin-7 on myocardial hypertrophy in hyperthyroidism-induced cardiomyopathy.

The purpose of this study was to investigate the effect of β-casomorphin-7 (β-CM-7) on myocardial hypertrophy (MH) in hyperthyroidism-induced cardiomyopathy in vivo and in vitro. Thirty C56BL/6 mice were randomly divided into three groups: control group, hyperthyroidism group, and β-CM-7 treatment group. An animal model of cardiac hypertrophy of hyperthyroid heart disease (HHD) was constructed by continuous intraperitoneal injection of 100 μg of L-thyroxine (L-Thy) for 28 days, and the serum TT3 and TT4 concentrations were measured. After that, myocardial specimens were collected to measure left and right ventricular MH index, and the myocardial cell structure was observed under hematoxylin and eosin (HE) staining. Thereafter, Masson staining was adopted to determine collagen volume fraction, and hydroxylamine method was used to measure superoxide dismutase (SOD) activity, Meanwhile, DTNB direct method was applied to measure GSH-Px activity, thio-malonylurea method was utilized to measure malondialdehyde (MDA) content, and the level of reactive oxygen species (ROS) was detected by flow cytometry. Finally, the expressions of oxidative stress (OS) and inflammation-related factors in vivo and the nuclear factor-κB (NF-κB) pathway in vitro were detected by Western blot and quantitative real-time polymerase chain reaction (qRT-PCR). Compared with those in control group, TT3 and TT4 were remarkably increased, the structure of myocardial cells was disordered, the interstitial fibrosis and the ventricular MH index were significantly increased, the OS and inflammatory responses were increased, and the NF-κB pathway was activated in the Hyperthyroidism group. In the β-CM-7 group, the content of TT3 and TT4 was decreased, the myocardial cell structure was slightly disturbed, the fibrosis and the ventricular MH index were reduced, OS and inflammatory response were reduced, and the NF-κB pathway was inhibited. β-CM-7 can prevent and treat MH in mice with L-Thy-induced HHD probably through regulating the NF-κB signaling pathway.

Dihydromyricetin Attenuates Myocardial Hypertrophy Induced by Transverse Aortic Constriction via Oxidative Stress Inhibition and SIRT3 Pathway Enhancement.

Dihydromyricetin (DMY), one of the flavonoids in vine tea, exerts several pharmacological actions. However, it is not clear whether DMY has a protective effect on pressure overload-induced myocardial hypertrophy. In the present study, male C57BL/6 mice aging 8–10 weeks were subjected to transverse aortic constriction (TAC) surgery after 2 weeks of DMY (250 mg/kg/day) intragastric administration. DMY was given for another 2 weeks after surgery. Blood pressure, myocardial structure, cardiomyocyte cross-sectional area, cardiac function, and cardiac index were observed. The level of oxidative stress in the myocardium was assessed with dihydroethidium staining. Our results showed that DMY had no significant effect on the blood pressure. DMY decreased inter ventricular septum and left ventricular posterior wall thickness, relative wall thickness, cardiomyocyte cross-sectional areas, as well as cardiac index after TAC. DMY pretreatment also significantly reduced arterial natriuretic peptide (ANP), brain natriuretic peptide (BNP) mRNA and protein expressions, decreased reactive oxygen species production and malondialdehyde (MDA) level, while increased total antioxidant capacity (T-AOC), activity of superoxide dismutase (SOD), expression of sirtuin 3 (SIRT3), forkhead-box-protein 3a (FOXO3a) and SOD2, and SIRT3 activity in the myocardium of mice after TAC. Taken together, DMY ameliorated TAC induced myocardial hypertrophy in mice related to oxidative stress inhibition and SIRT3 pathway enhancement.

Dihydromyricetin ameliorates transverse aortic constriction induced myocardial hypertrophy in mice via inhibition of oxidative stress

Dihydromyricetin ameliorates transverse aortic constriction induced myocardial hypertrophy in mice via inhibition of oxidative stress

Protective effect of hydrogen sulphide against myocardial hypertrophy in mice.

Cardiac hypertrophy is a critical component of phenotype in the failing heart. Recently, increasing evidence has demonstrated that oxidative stress plays an important role in the pathogenesis of myocardial hypertrophy. In the present study, we generated a mouse model of transverse aortic constriction (TAC) to investigate whether hydrogen sulfide (H2S) has protective effects against cardiac hypertrophy. Left ventricular structure was analyzed by two-dimensional echocardiography. Oxidative stress was evaluated by measuring malondialdehyde, superoxide dismutase, glutathione peroxidase and reactive oxygen specie in the myocardium. Angiotensin II (Ang-II) was used to induce cardiomyocyte hypertrophy. Neonatal rat cardiomyocytes pretreated with H2S donor sodium hydrosulfide prior to Ang-II exposure were used to determine the involvement of Nrf2 and PI3K/Akt pathway in the antioxidant effects of H2S. Our findings showed that H2S could protect against cardiac hypertrophy by attenuating oxidative stress. The antioxidant roles of H2S in myocardial hypertrophy probably depend on the activation of PI3K/Akt signaling, which consequently increases Nrf2 activity and HO-1 and GCLM expression. In summary, H2S may exert antioxidant effect on cardiac hypertrophy via PI3K/Akt-dependent activation of Nrf2 pathway.

Changes in endogenous sulfur dioxide pathway in angiotensin II- induced myocardial hypertrophy in mice

Objective To explore the changes in the endogenous sulfur dioxide (SO2) pathway in the myocardial hypertrophy induced by the angiotensin Ⅱ(Ang Ⅱ) in mice. Methods Fourteen healthy C57BL mice, 9 weeks old, were randomly divided into control group(n=7) and Ang Ⅱ group(n=7), and capsule osmotic pump with pre-loaded 9 g/L saline and Ang Ⅱ was implanted into the back of each mouse subcutaneously.After 2 weeks, the mice were executed.The heart weight/body weight (HW/BW) and the left heart weight/full heart weight (LVW/HW) of the mice were measured.The microstructure of the cardiac myocyte was observed by hematoxylin-eosin (HE) staining under the microscope.The expression of myocardial alpha myosin heavy chain (α-MHC) was detected by immunohistochemistry and Western blot methods.SO2 enzymes aspartate aminotransferase 1 (AAT1) and AAT2 protein expression were detected by Western blot method.Myocardial SO2 content and AAT activity were measured by high performance liquid chromatography with fluorimetric detection and colometric method. Results Compared with control group, the HW/BW and LVW/HW in mice of Ang Ⅱ group were significantly increased(all P<0.01), the cardiac myocytes were hypertrophy, and α-MHC positive staining in the cytoplasm of myocardium was weakened.Moreover, Western blot data showed that α-MHC protein expression in heart tissue of Ang Ⅱ-treated mice was decreased significantly (all P<0.05). Simultaneously, the data showed that AAT2 protein expression, SO2 content and AAT activity in heart tissue of Ang Ⅱ-treated mice were also decreased markedly[(1.093±0.131) μmol/g protein vs.(0.737±0.233) μmol/g protein, P<0.05; (7.979±1.317) U/mg protein vs.(6.470±0.516) U/mg protein, P<0.01]. Furthermore, there was a negative correlation between LVW/HW and cardiac SO2 content in heart tissue (r=-0.56, P<0.05). Conclusions Myocardial endogenous SO2/AAT2 pathway is down-regulated in the development of myocardial hypertrophy induced by Ang Ⅱ in mice. Key words: Myocardial hypertrophy; Sulfur dioxide; Angiotensin Ⅱ

Downregulated endogenous sulfur dioxide/aspartate aminotransferase pathway is involved in angiotensin II-stimulated cardiomyocyte autophagy and myocardial hypertrophy in mice

BackgroundThe study was designed to investigate if endogenous sulfur dioxide (SO2) was involved in cardiomyocyte autophagy and myocardial hypertrophy stimulated by angiotensin II (Ang II). MethodsThirty-two C57 mice were randomly divided into control, SO2, Ang II and Ang II+SO2 groups. Human myocardial cell line H9c2 was divided into four groups including control, SO2, Ang II and Ang II+SO2 groups. Blood pressure and myocardial hypertrophy of the mice were measured two weeks after Ang II administration. LC3 II/I ratio, and Beclin1, Atg4B and p62 expressions were determined both in vivo and in vitro. Autophagosome was observed in H9c2 cells with confocal microscope. Endogenous SO2 generation and aspartate aminotransferase (AAT) expression were measured. ResultsIn animal studies, hypertension and myocardial hypertrophy developed two weeks after Ang II administration. LC3 II/I ratio and Beclin1 and Atg4B expressions were markedly elevated (P all <0.05), but p62 expression was lowered (P<0.05) both in vivo and in vitro. Compared with control group, endogenous SO2 levels, AAT activity and AAT2 expression were obviously down-regulated (P all <0.05). However, SO2 donor significantly reduced Ang II-induced myocardial hypertrophy in mice. LC3 II/I ratio and Beclin1 and Atg4B expressions were down-regulated (P all <0.05) but p62 expression was significantly increased (P<0.05) in the presence of SO2 both in vivo and in vitro. ConclusionDown-regulated endogenous SO2/AAT2 pathway might be involved in the pathogenesis of myocardial hypertrophy. SO2 prevented Ang II -induced myocardial hypertrophy accompanied by down-regulating cardiomyocyte autophagy.

Effect and mechanism of polydatin on diabetic myocardial hypertrophy in mice

To observe the preventive effect of polydatin on diabetic myocardial hypertrophy in mice and discuss its and mechanism. The diabetic model was induced with low dose STZ (40 mg x kg(-1) x d(-1) x 5 d, ip) for five days in mice. The myocardial hypertrophy was determined by hypertrophy indexes (LVHI, left ventricular/right ventricle and septum), left ventricular/body weight (LV/BW), the histological examination and the mRNA expression of atrial natriuretic factor(ANF). The fast blood glucose(FBG), serum insulin and plasma hemoglobin A1c ( HbA1c) levels were detected, and then HOMA insulin resistance index ( HOMA. IR) was calculated. The mRNA and protein expressions were measured by qRT-PCR and western blotting, respectively. According to the results, the FBG of the model group exceeded 11.1 mmol x L(-1), with notable decrease in BW and significant increase in insulin, HbA1c and HOME. IR, suggesting the successful establishment and stability of the diabetic model. The increases in LVHI, LV/BW, cell surface and ANF mRNA indicated a myocardial hypertrophy in diabetic mice. Meanwhile, the model group showed decrease in mRNA and protein expressions of PPARβ and significant increase in NF-κB p65, COX-2 and iNOS expressions. After the preventation with PD (50, 100 mg x kg(-1) x d(-1)), diabetic mice showed increase in BW, reduction in the levels of FBG, insulin and HbA1 c, relief in insulin resistance and significant recovery in hypertrophy indexes, indicating PD has the protective effect in diabetic myocardial hypertrophy. Meanwhile, PD up-regulated the expression of PPARβ, inhibited the expressions of NF-κB p65, COX-2 and iNOS, demonstrating that PD's protective effect may be related to the activation of PPARβ and the inhibition of NF-κB, COX-2 and iNOS signaling pathways.

GW25-e1168 Chlorogenic acid prevents Isoproterenol-induced myocardial hypertrophy in mice in vivo

GW25-e1168 Chlorogenic acid prevents Isoproterenol-induced myocardial hypertrophy in mice in vivo

Fill a Gab(1) in Cardiac Hypertrophy Signaling

HomeCirculation ResearchVol. 93, No. 3Fill a Gab(1) in Cardiac Hypertrophy Signaling Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBFill a Gab(1) in Cardiac Hypertrophy SignalingSearch a Missing Link Between gp130 and ERK5 in Hypertrophic Remodeling in Heart Yibin Wang Yibin WangYibin Wang From the Division of Molecular Medicine, Department of Anesthesiology and Medicine, University of California, David Geffen School of Medicine, Los Angles, Calif. Search for more papers by this author Originally published8 Aug 2003https://doi.org/10.1161/01.RES.0000087333.88497.AECirculation Research. 2003;93:186–188Cardiac hypertrophy represents one of the most central issues in heart failure, involving many aspects of changes in cardiac myocyte from cellular morphology to gene expression and contractile function.1,2 Although the process is at the beginning compensatory in response to hemodynamic load or myocardial injury, cardiac hypertrophy is often followed by pathological remodeling in myocardium and a transition to overt heart failure.3 A large number of extracellular ligands, their cognate receptors and corresponding intracellular signal transduction pathways have been implicated in the hypertrophic process from both in vitro and in vivo studies.4–13 Among them, cardiotrophin-1 (CT-1) was discovered as a potent activator of cardiac hypertrophy14 that shares extensive sequence and functional similarities with leukemia inhibitory factor (LIF) as members of interleukin-6 (IL-6)–related cytokine family.15 LIF/CT-1 bind to gp130/LIF cytokine receptor β heterodimer and activate downstream signaling pathways, including members of signal transducer and activator of transcription (STATs), mitogen-activated protein (MAP) kinases such as extracellular signal–regulated kinases (ERK1/2), and phosphatidylinositol 3-kinase (PI3K)/Akt.15,16 Studies have demonstrated that both LIF and CT-1 promote myocyte hypertrophy, survival, and a unique pattern of embryonic/fetal gene induction.17–22 LIF and CT-1 expression and gp130 signaling also correlated with mechanical stress in myocytes in culture23 and human and experimental models of heart failure.24–30 More significantly, targeted inactivation of gp130 in ventricular myocytes via Cre-loxP–mediated tissue-specific knockout resulted in rapid chamber dilation and a significant increase in myocyte apoptosis upon pressure overload.31 All these findings underscore the potential function of gp130 signaling in myocyte remodeling and survival in response to mechanical stress.In addition to marker gene activation and antiapoptotic effects, gp130-mediated hypertrophy has a distinctive pattern of sarcomere organization. Unlike phenylephrine or endothelin-1 that induce hypertrophy response in cultured myocytes with enlarged cell size in all dimensions, LIF or CT-1 increases cell length by adding sarcomere units in a serial rather than parallel fashion.19 Such observation has prompted speculation that gp130 signaling may have a specific role in eccentric hypertrophy, a remodeling process more specifically associated with volume overload, as to concentric hypertrophy induced by pressure overload.1 A recent report by Nicol et al32 suggests that MEK5, an activator of big MAP kinase (BMK/ERK5), is capable to elicit serial assembly of sarcomere in myocytes and induces eccentric hypertrophy in transgenic hearts. They further demonstrate that MEK5/ERK5 is essential to LIF-induced myocyte elongation. However, the molecular mechanism underlying LIF/CT-1–induced MEK5/ERK5 activation via gp130 signal complex remains unclear. In this issue of Circulation Research, Nakaoka et al33 provide some interesting new evidence to suggest that a missing puzzle linking gp130 to MEK5/ERK5 pathway may have been found.It should not be a surprise that Grb2-associated binder-1 (Gab-1) is a prime suspect in the search for a functional linker between gp130 and downstream MAP kinase activation. Gab-1 is a member of the Gab/DOS (daughter of sevenless) family of scaffolding/docking molecules and contains a pleckstrin homology (PH) domain and potential SH2/SH3 binding motifs.34,35 Tyrosine-phosphorylated Gab-1 can interact with a number of signaling molecules, including p85 PI3K, phospholipase C-γ, and a src homology (SH) 2 domain–containing protein tyrosine phosphatase (SHP-2).36,37 Genetic inactivation Gab-1 leads to embryonic lethality and loss of ERK activation in response to growth factor stimulation, thus underscoring the importance of Gab-1 in MAP kinase activation via tyrosine kinase receptors and cytokine receptors.38 Since SHP-2 recruitment to gp130 is important to downstream MAP kinase activation,36 and SHP-2 is found to be a strong binding partner of Gab-1,35 it does not seem to be a far-fetched hunch that Gab-1 may also play a role in gp130-mediated MAP kinase activation in heart. In the present study,33 Nakaoka et al combined both biochemical and cellular studies to demonstrate that Gab-1 phosphorylation and SHP-2 binding were dependent on LIF stimulation and was required for ERK5 activation, selective marker gene regulation, and most interestingly sarcomere organization associated with myocyte elongation (Figure). In contrast, STAT3 activation was not affected by Gab-1/SHP-2 interaction, and activity of AKT and ERK1/2 was only partially affected, suggesting a rather specific role for Gab-1/SHP-2 interaction in gp130 dependent signaling in myocytes. This result is somewhat surprising because SHP-2 and JAK/STAT are shown to have reciprocal function downstream of gp130 and may reflect a unique signaling property in cardiomyocytes versus other cell types.39Download figureDownload PowerPointRole of Gab-1 in gp130-mediated activation of ERK5. Cytokine binding to gp130 triggers receptor dimerization, tyrosine phosphorylation of JAK, and SHP-2. Gab-1 is tyrosine-phosphorylated and translocated to form a complex with SHP-2 and other unknown signaling molecules, which leads to ERK5 activation and myocyte hypertrophy and elongation.Although the findings of the present report are consistent with the hypothesis that Gab-1 serves as a scaffold protein to link SHP-2 and its downstream signaling partner(s) into a functional signaling complex, it will remain speculative until all of its molecular components can be identified. Indeed, identification of the interacting partners of Gab-1 in cardiomyocytes will help to address many related questions. For example, which upstream kinase is part of the signaling complex that is responsible for ERK5 activation, whether and how SHP-2 phosphatase activity mediates downstream kinase activation, whether and how Gab-1/SHP-2 interaction affects other tyrosine kinase receptor–mediated signaling pathways and other gp130-mediated signaling. Obviously, finding Gab-1 will lead to many more puzzle pieces involved in the signaling network of cardiac hypertrophy.Perhaps an even more intriguing question from the present study is whether Gab-1/SHP-2 functions as a differential signaling switch that turns on eccentric hypertrophy. Since no effective therapy is available to treat this specific form of cardiomyopathy, the potential impact of identifying a responsible signaling pathway cannot be understated. A recent report from Yasukawa et al30 demonstrated that gp130-dependent signaling was highly induced by pressure overload along with a number of other signaling pathways, such as ERK1/2, p38, and AKT, but was negatively regulated by suppressor of cytokine signaling-3 (SOCS3), which was also induced by pressure overload and was capable of blocking almost all aspects of CT-1–induced myocyte hypertrophy. Furthermore, SOCS3 shares its preferred binding site on gp130 with the same docking site of SHP-2, suggesting that SOCS3 may compete and suppress Gab-1/SHP-2–mediated signaling from gp130 receptor.40 Therefore, in pressure-overloaded hearts, gp130-dependent signaling may have been suppressed by intrinsic inhibitor SOCS3 that channels the cardiac remodeling process toward a concentric form. By the same token, we can speculate that in volume-overloaded hearts, there might be a different balance between SOCS3 and Gab-1/SHP-2 signaling that favors ERK5 activation and leads to eccentric hypertrophy. Indeed, CT-1 has been found to be elevated in patients with valvular regurgitation but normal left ventricular systolic function.26 However, SOCS3 expression and the expression/phosphorylation/intracellular distribution of Gab-1 have not been fully characterized in an in vivo model of volume overload. Hopefully, the findings from Nakaoka et al33 will provide enough incentive and guidance to look into these questions in a relevant model system. Lastly, the study reported here represents only some preliminary investigation exclusively performed in cultured myocytes. Manipulation of Gab-1 expression and its interaction with SHP-2 in intact heart will be necessary to further establish its role in gp130-mediated cardiac remodeling. In that regard, sophisticated genetic approaches are already developed to achieve cardiac-specific and developmental stage–regulated manipulation to overcome embryonic lethality and to provide more concrete evidence for the physiological role of Gab-1 in cardiac hypertrophy.13 There is no doubt that future studies will lead us to more missing links in the complex signaling network of cardiac hypertrophy.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.FootnotesCorrespondence to Yibin Wang, Division of Molecular Medicine, Department of Anesthesiology and Medicine, University of California, David Geffen School of Medicine, Los Angles, CA 90095. E-mail [email protected] References 1 Lorell BH, Carabello BA. Left ventricular hypertrophy: pathogenesis, detection, and prognosis. Circulation. 2000; 102: 470–479.CrossrefMedlineGoogle Scholar2 Houser SR, Piacentino V 3rd, Weisser J. 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Inta I, Weber D, Grundt C, Veltkamp R, Winteroll S, Auffarth G, Bettendorf M, Lemmer B and Schwaninger M (2009) Correlation of soluble gp130 serum concentrations with arterial blood pressure, Journal of Hypertension, 10.1097/HJH.0b013e32831e9948, 27:3, (527-534), Online publication date: 1-Mar-2009. IZAWA Y, YOSHIZUMI M, ISHIZAWA K, FUJITA Y, KONDO S, KAGAMI S, KAWAZOE K, TSUCHIYA K, TOMITA S and TAMAKI T (2007) Big Mitogen-Activated Protein Kinase 1 (BMK1)/Extracellular Signal Regulated Kinase 5 (ERK5) Is Involved in Platelet-Derived Growth Factor (PDGF)-Induced Vascular Smooth Muscle Cell Migration, Hypertension Research, 10.1291/hypres.30.1107, 30:11, (1107-1117), . August 8, 2003Vol 93, Issue 3 Advertisement Article InformationMetrics https://doi.org/10.1161/01.RES.0000087333.88497.AEPMID: 12907663 Originally publishedAugust 8, 2003 Keywordscardiac hypertrophyscaffold proteinGab-1extracellular signal-regulated kinase 5cytokine signalingPDF download Advertisement

Enhanced cardiomyocyte DNA synthesis during myocardial hypertrophy in mice expressing a modified TSC2 transgene.

Tuberous sclerosis complex (TSC) is a rare genetic disorder characterized by the appearance of benign tumors in multiple organs, including the heart. Disease progression is accompanied by homozygous mutation at 1 of 2 loci (designated TSC1 or TSC2), leading to the suggestion that these genes function as tumor suppressors. In this study, we generated a series of TSC2 cDNAs in which one or more structural motifs were deleted, with the hope that expression of the modified gene product would override the growth-inhibitory activity of the endogenous TSC2 gene product. Several of the modified cDNAs enhanced growth rate, increased endocytosis, and promoted aberrant protein trafficking when expressed in NIH-3T3 cells, thereby mimicking phenotypes typical of TSC2-deficient cells. Surprisingly, targeted expression of the most potent TSC2 cDNA to the heart did not perturb cardiac development. However, the level of cardiomyocyte DNA synthesis in adult transgenic mice was elevated >35-fold during isoproterenol-induced hypertrophy compared with their nontransgenic siblings. These results suggest that alteration of TSC2 gene activity in combination with beta-adrenergic stimulation can reactivate the cell cycle in a limited number of terminally differentiated adult cardiomyocytes.

Continuous activation of gp130, a signal-transducing receptor component for interleukin 6-related cytokines, causes myocardial hypertrophy in mice.

To investigate the physiological roles of gp130 in detail and to determine the pathological consequence of abnormal activation of gp130, transgenic mice having continuously activated gp130 were created. This was carried out by mating mice from interleukin 6 (IL-6) and IL-6 receptor (IL-6R) transgenic lines. Offspring overexpressing both IL-6 and IL-6R showed constitutive tyrosine phosphorylation of gp130 and a downstream signaling molecule, acute phase response factor/signal transducer and activator of transcription 3. Surprisingly, the distinguishing feature of such offspring was hypertrophy of ventricular myocardium and consequent thickened ventricular walls of the heart, where gp130 is also expressed, in adulthood. Transgenic mice overexpressing either IL-6 or IL-6R alone did not show detectable myocardial abnormalities. Neonatal heart muscle cells from normal mice, when cultured in vitro, enlarged in response to a combination of IL-6 and a soluble form of IL-6R. The results suggest that activation of the gp130 signaling pathways leads to cardiac hypertrophy and that these signals might be involved in physiological regulation of myocardium.