Negative Regulator Of Cardiac Hypertrophy Research Articles

Identification of a long noncoding RNA Gm17501 as a novel negative regulator of cardiac hypertrophy

Pathological cardiac hypertrophy is an independent risk factor for the development of heart failure. Long noncoding RNAs (lncRNAs), an emerging class of non-protein-coding transcripts, are involved in regulation of multiple cardiac diseases through diverse molecular mechanism, whereas the role of cytoplasmic lncRNAs in regulating cardiac hypertrophy remains unclear. In this study, we identified a novel and functional long noncoding RNA Gm17501, which was predominantly expressed in the cytoplasm of cardiomyocytes. The expression level of lncRNA Gm17501 was altered in cardiac hypertrophy induced by pressure overload and phenylephrine treatment. Moreover, lncRNA Gm17501 expression was decreased in the heart tissue of patients with heart failure. Silencing lncRNA Gm17501 aggravated cardiac hypertrophy under pathological stress. Inhibition of lncRNA Gm17501 did not alter the expression of nearby genes but decreased mRNA level of calcium handling proteins which were involved in cardiac contraction. Therefore, the cytoplasmic lncRNA Gm17501 might protect cardiomyocytes against hypertrophy, possibly by maintaining calcium signaling pathway.

Ser9 phosphorylation of GSK-3β promotes aging in the heart through suppression of autophagy.

Introduction:Glycogen synthase kinase-3β (GSK-3β) is a serine/threonine kinase and a negative regulator of cardiac hypertrophy. Phosphorylation of GSK-3β at Ser9 negatively regulates its kinase activity. The role of GSK-3β in cardiac aging remains poorly understood.Aim:The study aimed to elucidate the role of GSK-3β Ser9 phosphorylation in mediating cardiac aging and the underlying mechanism.Methods and Results:Phosphorylation of GSK-3β at Ser9 and the levels of β-catenin and Mcl-1 were increased in the mouse heart during aging, suggesting that GSK-3β is inactivated during aging in the heart. Age-induced cardiac hypertrophy, fibrosis, left ventricular dysfunction, and increases in cardiomyocyte apoptosis and senescence were all attenuated in constitutively active GSK-3βS9A knock-in (KI) mice compared to littermate wild type mice. Although autophagy is inhibited in the heart during aging, KI of GSK-3βS9A reversed the age-associated decline in autophagy in the mouse heart. GSK-3β directly phosphorylates Ulk1, a regulator of autophagy, at Ser913, thereby stimulating autophagy in cardiomyocytes. Ulk1Ser913A KI mice exhibited decreased autophagic flux and increased senescence in cardiomyocytes.Conclusion:Our results suggest that GSK-3β is inactivated during aging through Ser9 phosphorylation, which in turn plays an important role in mediating cardiac aging. GSK-3β promotes autophagy through phosphorylation of Ulk1 at Ser913, which in turn prevents aging in the heart.

Crucial Role of Mammalian Glutaredoxin 3 in Cardiac Energy Metabolism in Diet-induced Obese Mice Revealed by Transcriptome Analysis.

Obesity is often associated with metabolic dysregulation and oxidative stress with the latter serving as a possible unifying link between obesity and cardiovascular complications. Glutaredoxins (Grxs) comprise one of the major antioxidant systems in the heart. Although Grx3 has been shown to act as an endogenous negative regulator of cardiac hypertrophy and heart failure, its metabolic impact on cardiac function in diet-induced obese (DIO) mice remains largely unknown. In the present study, analysis of Grx3 expression indicated that Grx3 protein levels, but not mRNA levels, were significantly increased in the hearts of DIO mice. Cardiac-specific Grx3 deletion (Grx3 CKO) mice were viable and grew indistinguishably from their littermates after being fed a high fat diet (HFD) for one month, starting at 2 months of age. After being fed with a HFD for 8 months (starting at 2 months of age); however, Grx3 CKO DIO mice displayed left ventricular systolic dysfunction with a significant decrease in ejection fraction and fractional shortening that was associated with heart failure. ROS production was significantly increased in Grx3 CKO DIO cardiomyocytes compared to control cells. Gene expression analysis revealed a significant decline in the level of transcripts corresponding to genes associated with processes such as fatty acid uptake, mitochondrial fatty acid transport and oxidation, and citrate cycle in Grx3 CKO DIO mice compared to DIO controls. In contrast, an increase in the level of transcripts corresponding to genes associated with glucose uptake and utilization were found in Grx3 CKO DIO mice compared to DIO controls. Taken together, these findings indicate that Grx3 may play a critical role in redox balance and as a metabolic switch in cardiomyocytes contributing to the development and progression of heart failure.

MiR-625-5p Inhibits Cardiac Hypertrophy Through Targeting STAT3 and CaMKII.

Cardiac hypertrophy is an adaptive cardiac response to heart stress. Sustained cardiac hypertrophy indicates higher risk of heart failure. Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been proved to be a key regulator of cardiac hypertrophy, but its mechanism remains largely unknown. Our study proposed to explore the regulatory mechanism of CaMKII in cardiac hypertrophy. We validated that CaMKII was upregulated in cardiac hypertrophy models in vivo and in vitro and that knockdown of CaMKII attenuated Ang II-induced cardiac hypertrophy in vitro. Furthermore, we demonstrated that signal transducer and activator of transcription 3 (STAT3) was highly expressed in cardiac hypertrophy and could stimulate the transactivation of CaMKII. Moreover, we predicted through TargetScan and confirmed that miR-625-5p targeted and inhibited STAT3 so as to reduce the expression of CaMKII. Interestingly, we also found that miR-625-5p directly targeted CaMKII and inhibited its expression. Rescue assays suggested that miR-625-5p attenuated Ang II-induced cardiac hypertrophy through CaMKII/STAT3. Consequently, this study elucidated that miR-625-5p inhibited cardiac hypertrophy through targeting STAT3 and CaMKII, suggesting miR-625-5p as a novel negative regulator of cardiac hypertrophy. Graphical abstract [Figure: see text].

Long noncoding RNA MAGI1-IT1 regulates cardiac hypertrophy by modulating miR-302e/DKK1/Wnt/beta-catenin signaling pathway.

Cardiac hypertrophy (CH) is an adaptive cardiac response to overload whose decompensation eventually leads to heart failure or sudden death. Recently, accumulating studies have indicated the implication of long noncoding RNAs (lncRNAs) in CH progression. MAGI1-IT1 is a newly-identified lncRNA that is highly associated with CH, while its specific role in CH progression remains masked. In this study, we uncovered that MAGI1-IT1 was distinctly downregulated in angiotensin (Ang) II-induced hypertrophic H9c2 cells. Also, MAGI1-IT1 overexpression in Ang II-treated H9c2 cells strikingly abolished the enlarged surface area and the enhanced levels of hypertrophic markers such as ANP, BNP, and β-MHC. Mechanically, we found MAGI1-IT1 sponged miR-302e which was identified as a hypertrophy-facilitator here, and that miR-302e upregulation countervailed the inhibition of MAGI1-IT1 overexpression on hypertrophic cells. Moreover, it was confirmed that MAGI1-IT1 boosted DKK1 expression by absorbing miR-302e. Subsequently, we also illustrated that MAGI1-IT1 inactivated Wnt/beta-catenin signaling through a DKK1-dependent pathway. Finally, both the DKK1 inhibition and LiCI (Wnt activator) supplement abrogated the hypertrophy-suppressive impact of MAGI1-IT1 on Ang II-simulated hypertrophic H9c2 cells. Jointly, our findings disclosed that MAGI1-IT1 functioned as a negative regulator in CH through inactivating Wnt/beta-catenin pathway via targeting miR-302e/DKK1 axis, revealing a novel road for CH treatment.

LncRNA TUG1 contributes to cardiac hypertrophy via regulating miR-29b-3p.

Cardiac hypertrophy with maladjusted cardiac remodeling is the leading cause of heart failure. In the past decades, long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been proved to exert multiple functions in cellular biological behaviors; however, their role in cardiac hypertrophy remains largely unclear. Presently, we first obtained hypertrophic H9c2 cells by treating with angiotensin II (Ang II) and uncovered upregulation of lncRNA taurine upregulated gene 1 (TUG1) in such H9c2 cells. Then, we demonstrated that silencing TUG1 attenuated Ang II-induced cardiac hypertrophy. Besides, a strong interactivity of TUG1 with miR-29b-3p at the putative sites was validated, suggesting that TUG1 was an endogenous sponge of miR-29b-3p in H9c2 cells. Additionally, the expression of miR-29b-3p was strikingly reduced by TUG1 upregulation and also inhibited under Ang II treatment, whereas it was restored after silencing TUG1 in hypertrophic cells. Also, we proved miR-29b-3p as a negative regulator in cardiac hypertrophy. Finally, miR-29b-3p inhibition abolished the anti-hypertrophy effect of TUG1 depletion in Ang II-treated H9c2 cells. Collectively, our findings confirmed that TUG1 functioned as a positive modulator of cardiac hypertrophy via sponging miR-29b-3p, indicating that TUG1 might serve as a potential target for the treatment of cardiac hypertrophy and even heart failure.

1.25 Dihydroxyvitamin D3 Attenuates Hypertrophy Markers in Cardiomyoblast H9c2 Cells: Evaluation of Sirtuin3 mRNA and Protein Level.

Background: The cellular and molecular mechanisms of cardioprotective effects of Vitamin D are poorly understood. Given the essential role of sirtuin-3 (SIRT3) as an endogenous negative regulator of cardiac hypertrophy, this study was designed to investigate the effect of 1, 25-dihydroxyvitamin D3 (calcitriol) on hypertrophy markers and SIRT3 mRNA and protein levels following angiotensin II induced - hypertrophy in cardiomyoblast H9c2 cells. Methods: Rat cardiomyoblast H9c2 cells were treated for 48 hr with angiotensin II alone (Ang group) or in combination with 1, 10 and 100 nM of calcitriol (C+Ang groups). Intact cells served as control (Ctl). The cell area was measured using methylene bluestaining. Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and SIRT3 transcription levels were measured by real time RT-PCR. SIRT3 protein expression was evaluated using western blot technique. Results: The results showed that in Ang group cell size was increase by 128.4±15% (P<0.001 vs. Ctl) whereas in C100+Ang group it was increased by 21.3±6% (P<0.001 vs. Ang group). Calcitriol pretreatment decreased ANP mRNA level significantly (P<0.05) in comparison with Ang group (Ang: 75.5±15%, C100+Ang: 19.2±9%). There were no significant differences between Ang group and cells pretreated with 1 and 10 nM of calcitriol. SIRT3at mRNA and protein levels did not change significantly among the experimental groups. Conclusions: In conclusion, pretreatment with calcitriol (100 nM) prevents Ang II-induced hypertrophy in cardiomyoblast H9c2 cells. This probably occurs through other pathways except SIRT3 upregulation.

Regenerative Capacity of Endogenous Factor: Growth Differentiation Factor 11; a New Approach of the Management of Age-Related Cardiovascular Events.

Aging is a complicated pathophysiological process accompanied by a wide array of biological adaptations. The physiological deterioration correlates with the reduced regenerative capacity of tissues. The rejuvenation of tissue regeneration in aging organisms has also been observed after heterochronic parabiosis. With this model, it has been shown that exposure to young blood can rejuvenate the regenerative capacity of peripheral tissues and brain in aged animals. An endogenous compound called growth differentiation factor 11 (GDF11) is a circulating negative regulator of cardiac hypertrophy, suggesting that raising GDF11 levels could potentially treat or prevent cardiac diseases. The protein GDF11 is found in humans as well as animals. The existence of endogenous regulators of regenerative capacity, such as GDF11, in peripheral tissues and brain has now been demonstrated. It will be important to investigate the mechanisms with therapeutic promise that induce the regenerative effects of GDF11 for a variety of age-related diseases.

ADAM23 in Cardiomyocyte Inhibits Cardiac Hypertrophy by Targeting FAK - AKT Signaling.

BackgroundCardiac hypertrophy has been recognized as an important independent risk factor for the development of heart failure and increases the risk of cardiac morbidity and mortality. A disintegrin and metalloprotease 23 (ADAM23), a member of ADAM family, is involved in cancer and neuronal differentiation. Although ADAM23 is expressed in the heart, the role of ADAM23 in the heart and in cardiac diseases remains unknown.Methods and ResultsWe observed that ADAM23 expression is decreased in both failing human hearts and hypertrophic mice hearts. Cardiac‐specific conditional ADAM23‐knockout mice significantly exhibited exacerbated cardiac hypertrophy, fibrosis, and dysfunction, whereas transgenic mice overexpressing ADAM23 in the heart exhibited reduced cardiac hypertrophy in response to pressure overload. Consistent results were also observed in angiotensin II‐induced neonatal rat cardiomyocyte hypertrophy. Mechanistically, ADAM23 exerts anti‐hypertrophic effects by specifically targeting the focal adhesion kinase‐protein kinase B (FAK‐AKT) signaling cascade. Focal adhesion kinase inactivation by inhibitor (PF‐562271) greatly reversed the detrimental effects in ADAM23‐knockout mice subjected to aortic banding.ConclusionAltogether, we identified ADAM23 as a negative regulator of cardiac hypertrophy through inhibiting focal adhesion kinase‐protein kinase B signaling pathway, which could be a promising therapeutic target for this malady.

GDF11 Modulates Ca2+-Dependent Smad2/3 Signaling to Prevent Cardiomyocyte Hypertrophy.

Growth differentiation factor 11 (GDF11), a member of the transforming growth factor-β family, has been shown to act as a negative regulator in cardiac hypertrophy. Ca2+ signaling modulates cardiomyocyte growth; however, the role of Ca2+-dependent mechanisms in mediating the effects of GDF11 remains elusive. Here, we found that GDF11 induced intracellular Ca2+ increases in neonatal rat cardiomyocytes and that this response was blocked by chelating the intracellular Ca2+ with BAPTA-AM or by pretreatment with inhibitors of the inositol 1,4,5-trisphosphate (IP3) pathway. Moreover, GDF11 increased the phosphorylation levels and luciferase activity of Smad2/3 in a concentration-dependent manner, and the inhibition of IP3-dependent Ca2+ release abolished GDF11-induced Smad2/3 activity. To assess whether GDF11 exerted antihypertrophic effects by modulating Ca2+ signaling, cardiomyocytes were exposed to hypertrophic agents (100 nM testosterone or 50 μM phenylephrine) for 24 h. Both treatments increased cardiomyocyte size and [3H]-leucine incorporation, and these responses were significantly blunted by pretreatment with GDF11 over 24 h. Moreover, downregulation of Smad2 and Smad3 with siRNA was accompanied by inhibition of the antihypertrophic effects of GDF11. These results suggest that GDF11 modulates Ca2+ signaling and the Smad2/3 pathway to prevent cardiomyocyte hypertrophy.

Kruppel-Like Factor 15 Is Critical for the Development of Left Ventricular Hypertrophy.

Left ventricular hypertrophy (LVH) is an independent risk factor for adverse cardiovascular events and is often present in patients with hypertension. Treatment to reduce blood pressure and regress LVH is key to improving health outcomes, but currently available drugs have only modest cardioprotective effects. Improved understanding of the molecular mechanisms involved in the development of LVH may lead to new therapeutic targets in the future. There is now compelling evidence that the transcription factor Kruppel-like factor 15 (KLF15) is an important negative regulator of cardiac hypertrophy in both experimental models and in man. Studies have reported that loss or suppression of KLF15 contributes to LVH, through lack of inhibition of pro-hypertrophic transcription factors and stimulation of trophic and fibrotic signaling pathways. This review provides a summary of the experimental and human studies that have investigated the role of KLF15 in the development of cardiac hypertrophy. It also discusses our recent paper that described the contribution of genetic variants in KLF15 to the development of LVH and heart failure in high-risk patients.

The lncRNA Plscr4 Controls Cardiac Hypertrophy by Regulating miR-214.

Cardiac hypertrophy accompanied by maladaptive cardiac remodeling is the uppermost risk factor for the development of heart failure. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have various biological functions, and their vital role in the regulation of cardiac hypertrophy still needs to be explored. In this study, we demonstrated that lncRNA Plscr4 was upregulated in hypertrophic mice hearts and in angiotensin II (Ang II)–treated cardiomyocytes. Next, we observed that overexpression of Plscr4 attenuated Ang II-induced cardiomyocyte hypertrophy. Conversely, the inhibition of Plscr4 gave rise to cardiomyocyte hypertrophy. Furthermore, overexpression of Plscr4 attenuated TAC (transverse aortic constriction)-induced cardiac hypertrophy. Finally, we demonstrated that Plscr4 acted as an endogenous sponge of miR-214 and forced expression of Plscr4 downregulated miR-214 expression to promote Mfn2 and attenuate hypertrophy. In contrast, knockdown of Plscr4 upregulated miR-214 to induce cardiomyocyte hypertrophy. Additionally, luciferase assay showed that miR-214 was the direct target of Plscr4, and overexpression of miR-214 counteracted the anti-hypertrophy effect of Plscr4. Collectively, these findings identify Plscr4 as a negative regulator of cardiac hypertrophy in vivo and in vitro due to its regulation of the miR-214-Mfn2 axis, suggesting that Plscr4 might act as a therapeutic target for the treatment of cardiac hypertrophy and heart failure.

Herpud1 negatively regulates pathological cardiac hypertrophy by inducing IP3 receptor degradation

Cardiac hypertrophy is an adaptive response triggered by pathological stimuli. Regulation of the synthesis and the degradation of the Ca2+ channel inositol 1,4,5-trisphosphate receptor (IP3R) affects progression to cardiac hypertrophy. Herpud1, a component of the endoplasmic reticulum-associated degradation (ERAD) complex, participates in IP3R1 degradation and Ca2+ signaling, but the cardiac function of Herpud1 remains unknown. We hypothesize that Herpud1 acts as a negative regulator of cardiac hypertrophy by regulating IP3R protein levels. Our results show that Herpud1-knockout mice exhibit cardiac hypertrophy and dysfunction and that decreased Herpud1 protein levels lead to elevated levels of hypertrophic markers in cultured rat cardiomyocytes. In addition, IP3R levels were elevated both in Herpud1-knockout mice and Herpud1 siRNA-treated rat cardiomyocytes. The latter treatment also led to elevated cytosolic and nuclear Ca2+ levels. In summary, the absence of Herpud1 generates a pathological hypertrophic phenotype by regulating IP3R protein levels. Herpud1 is a novel negative regulator of pathological cardiac hypertrophy.

MicroRNA‐101b attenuates cardiomyocyte hypertrophy by inhibiting protein kinase C epsilon signaling

Previously, a surgical regression model identified microRNA-101b (miR-101b) as a potential inhibitor of cardiac hypertrophy. Here, we investigated the antihypertrophic mechanism of miR-101b using neonatal rat ventricular myocytes. miR-101b markedly suppressed agonist-induced cardiac hypertrophy as shown by cell size and fetal gene expression. By systems biology approaches, we identified protein kinase C epsilon (PKCε) as the major target of miR-101b. Our results from qRT-PCR, western blot, and luciferase reporter assays confirm that PKCε is a direct target of miR-101b. In addition, we found that effectors downstream of PKCε (p-AKT, p-ERK1/2, p-NFAT, and p-GSK3β) are also affected by miR-101b. Our study reveals a novel inhibitory mechanism for miR-101b as a negative regulator of cardiac hypertrophy.

The H19 long noncoding RNA is a novel negative regulator of cardiomyocyte hypertrophy.

The H19 lncRNA, a highly abundant and conserved imprinted gene, has been implicated in many essential biological processes and diseases. However, the function of H19 in the heart remains unknown. In this study, we investigated the function and underlying mechanism of H19 in regulating cardiomyocyte hypertrophy. We first detected the expression of H19 and its encoded miR-675 in both normal and diseased hearts and verified their up-regulations in pathological cardiac hypertrophy and heart failure. Adenovirus-mediated expression and a siRNA-mediated silence of H19 showed that H19 overexpression reduced cell size both at baseline and in response to phenylephrine, whereas knock-down of H19 induced cardiomyocyte hypertrophy. Overexpression or knock-down of miR-675 in cardiomyocytes demonstrated that miR-675 also inhibited cardiomyocyte hypertrophy. Moreover, inhibition of miR-675 reversed the reduction of cardiomyocyte size in H19-overexpressing cardiomyocytes, while infection with an adenovirus carrying H19 fragment without pre-miR-675 (H19-Tru) or with mutant sequences of pre-miR-675 (H19-Mut) failed to reduce cardiomyocyte size, indicating that miR-675 mediated the inhibitory effect of H19 on cardiomyocyte hypertrophy. We also identified that CaMKIIδ was a direct target of miR-675 and partially mediated the effect of H19 on cardiomyocyte hypertrophy. Furthermore, in vivo silencing of miR-675 using a specific antagomir in a pressure overload-induced mouse model of heart failure increased cardiac CaMKIIδ expression and exacerbated cardiac hypertrophy. These findings reveal a novel function of H19-miR-675 axis targeting CaMKIIδ as a negative regulator of cardiac hypertrophy, suggesting its potential therapeutic role in cardiac diseases.

Cardiac-Specific EPI64C Blunts Pressure Overload–Induced Cardiac Hypertrophy

The calcium-responsive molecule, calcineurin, has been well characterized to play a causal role in pathological cardiac hypertrophy over the past decade. However, the intrinsic negative regulation of calcineurin signaling during the progression of cardiomyocyte hypertrophy remains enigmatic. Herein, we explored the role of EPI64C, a dual inhibitor of both Ras and calcineurin signaling during T-cell activation, in pressure overload-induced cardiac hypertrophy. We generated a cardiac-specific Epi64c conditional knockout mouse strain and showed that loss of Epi64c remarkably exacerbates pressure overload-induced cardiac hypertrophy. In contrast, EPI64C gain-of-function in cardiomyocyte-specific Epi64c transgenic mice exerts potent protective effects against cardiac hypertrophy. Mechanistically, the cardioprotective effects of EPI64C are largely attributed to the disrupted calcineurin signaling but are independent of its Ras suppressive capability. Molecular studies have indicated that the 406 to 446 C-terminal amino acids in EPI64C directly bind to the 287 to 337 amino acids in the catalytic domain of calcineurin, which is responsible for the EPI64C-mediated suppressive effects. We further extrapolated our studies to cynomolgus monkeys and showed that gene therapy based on lentivirus-mediated EPI64C overexpression in the monkey hearts blunted pressure overload-induced cardiac hypertrophy. Our study thus identified EPI64C as a novel negative regulator in cardiac hypertrophy by targeting calcineurin signaling and demonstrated the potential of gene therapy and drug development for treating cardiac hypertrophy.

Cardiac Stim1 Silencing Impairs Adaptive Hypertrophy and Promotes Heart Failure Through Inactivation of mTORC2/Akt Signaling.

Stromal interaction molecule 1 (STIM1) is a dynamic calcium signal transducer implicated in hypertrophic growth of cardiomyocytes. STIM1 is thought to act as an initiator of cardiac hypertrophic response at the level of the sarcolemma, but the pathways underpinning this effect have not been examined. To determine the mechanistic role of STIM1 in cardiac hypertrophy and during the transition to heart failure, we manipulated STIM1 expression in mice cardiomyocytes by using in vivo gene delivery of specific short hairpin RNAs. In 3 different models, we found that Stim1 silencing prevents the development of pressure overload-induced hypertrophy but also reverses preestablished cardiac hypertrophy. Reduction in STIM1 expression promoted a rapid transition to heart failure. We further showed that Stim1 silencing resulted in enhanced activity of the antihypertrophic and proapoptotic GSK-3β molecule. Pharmacological inhibition of glycogen synthase kinase-3 was sufficient to reverse the cardiac phenotype observed after Stim1 silencing. At the level of ventricular myocytes, Stim1 silencing or inhibition abrogated the capacity for phosphorylation of Akt(S473), a hydrophobic motif of Akt that is directly phosphorylated by mTOR complex 2. We found that Stim1 silencing directly impaired mTOR complex 2 kinase activity, which was supported by a direct interaction between STIM1 and Rictor, a specific component of mTOR complex 2. These data support a model whereby STIM1 is critical to deactivate a key negative regulator of cardiac hypertrophy. In cardiomyocytes, STIM1 acts by tuning Akt kinase activity through activation of mTOR complex 2, which further results in repression of GSK-3β activity.

MiR-96 inhibits cardiac hypertrophy by targeting growth factor receptor-bound 2

Increasing evidence has indicated that microRNAs are involved in the pathogenesis of cardiac hypertrophy. However, whether miR-96 is involved in heart diseases, particularly cardiac hypertrophy, remains unclear. In this study, we found that miR-96 is a negative regulator of cardiac hypertrophy. In primary cardiomyocytes, overexpression of miR-96 inhibited phenylephrine-induced cardiomyocyte hypertrophy and decreased the mRNA expression of cardiac hypertrophy markers such as atrial natriuretic factor and β-myosin heavy chain. Interestingly, we found that growth factor receptor-bound 2 is a direct target of miR-96, which is a negative regulator of cardiac hypertrophy. Overexpression of miR-96 in cardiomyocytes led to reduced growth factor receptor-bound 2 expression. More importantly, miR-96 repressed the extracellular-regulated protein kinase signaling pathway by targeting growth factor receptor-bound 2 in cardiomyocytes. Our data demonstrate that miR-96 is a negative regulator of cardiac hypertrophy and extracellular-regulated protein kinase signaling, thus offering a new therapeutic strategy for cardiac hypertrophy.

Hydrogen Sulfide and SIRT3 Gene, the Strong Preventive and Therapeutic Agent in Aging and Age Related Diseases

There are seven SIRT isoforms in mammals, with different biological activities including gene regulation, metabolism and apoptosis. Despite recent controversy about sirtuins function in some organisms, among them SIRT3 is the only sirtuin whose increased expression has been shown to correlate with an extended life span in humans. SIRT3 is a member of the sirtuin family of NAD+ dependent deacetylases, which is localized to the mitochondria and is enriched in kidney, brown adipose tissue, heart, and other metabolically active tissues. It is an endogenous negative regulator of cardiac hypertrophy, which protects hearts by suppressing cellular levels of ROS and modulates mitochondrial intermediary metabolism and fatty acid utilization during fasting. Another one, Hydrogen sulfide is produced within the human body, and relaxes the vascular endothelium and smooth muscle cells, which is important to maintaining clean arteries as one age. It functions as an antioxidant and inhibits expression of pro-inflammatory factors, all of which imply an important role in aging and age-associated diseases. The aim of this review is to find out the anti aging properties of SIRT3 and H2S that can be used to extend the life span of human as a preventive and therapeutic agent.

Interferon Regulatory Factor 9 Protects Against Cardiac Hypertrophy by Targeting Myocardin

Pathological cardiac hypertrophy is a major risk factor for heart failure. In this study, we identified interferon regulatory factor 9 (IRF9), a member of the IRF family, as a previously unidentified negative regulator of cardiac hypertrophy. The level of IRF9 expression was remarkably elevated in the hearts from animals with aortic banding-induced cardiac hypertrophy. IRF9-deficient mice exhibited pronounced cardiac hypertrophy after pressure overload, as demonstrated by increased cardiomyocyte size, extensive fibrosis, reduced cardiac function, and enhanced expression of hypertrophy markers, whereas transgenic mice with cardiac-specific overexpression of murine IRF9 exhibited a significant reduction in the hypertrophic response. Mechanistically, IRF9 competes with p300 for binding to the transcription activation domain of myocardin, a coactivator of serum response factor (SRF). This interaction markedly suppresses the transcriptional activity of myocardin because IRF9 overexpression strongly inhibits the ability of myocardin to activate CArG box-dependent reporters. These results provide compelling evidence that IRF9 inhibits the development of cardiac hypertrophy by suppressing the transcriptional activity of myocardin in the heart.