Molecular Mechanisms Of Cardiac Hypertrophy Research Articles

LncRNA Gm15834 Aggravates Cardiac Hypertrophy by Interacting with Sam68 and Activating NF-κB Mediated Inflammation.

Cardiac hypertrophy is the common pathological process of multiple cardiovascular diseases. However, the molecular mechanisms of cardiac hypertrophy are unclear. Long non-coding RNA (lncRNA), a newly discovered type of transcript that has been demonstrated to function as crucial regulators in the development of cardiovascular diseases. This study revealed a novel regulatory pathway of lncRNA in cardiac hypertrophy. The cardiac hypertrophy models were established by transverse aortic constriction (TAC) in mice and angiotensin II (Ang II) in HL-1 cardiomyocytes. Adeno-associated virus 9 (AAV9) in vivo and lncRNA Gm15834 and shRNA plasmids in vitro were used to overexpress and knock down lncRNA Gm15834. The myocardial tissue structure, cardiomyocyte area, cardiac function, protein expressions, and binding of lncRNA Gm15834 and Src-associated substrate during mitosis of 68 KDa (Sam68) were detected by hematoxylin and eosin (HE) staining, immunofluorescence staining, echocardiography, western blot and RNA immunoprecipitation (RIP), respectively. In cardiac hypertrophy models, inhibiting lncRNA Gm15834 could decrease Sam68 expression and nuclear factor kappa-B (NF-κB) mediated inflammatory activities in vivo and in vitro, but overexpressing lncRNA Gm15834 showed the opposite results. RIP experiments validated the binding activities between lncRNA Gm15834 and Sam68. Overexpression of Sam68 could counteract the anti-hypertrophy effects of lncRNA Gm15834 knockdown. Meanwhile, in vivo inhibition of lncRNA Gm15834 could inhibit Sam68 expression, reduce NF-κB mediated inflammatory activity and attenuate cardiac hypertrophy. Our study revealed a novel regulatory axis of cardiac hypertrophy, which comprised lncRNA Gm15834/Sam68/NF-κB/inflammation, shedding a new light for identifying therapy target of cardiac hypertrophy in clinic.

PM2.5-induced iron homeostasis imbalance triggers cardiac hypertrophy through ferroptosis in a selective autophagy crosstalk manner

Exposure to PM2.5 is correlated with cardiac remodeling, of which cardiac hypertrophy is one of the main clinical manifestations. Ferroptosis plays an important role in cardiac hypertrophy. However, the potential mechanism of PM2.5-induced cardiac hypertrophy through ferroptosis remains unclear. This study aimed to explore the molecular mechanism of cardiac hypertrophy caused by PM2.5 and the intervention role of MitoQ involved in this process. The results showed that PM2.5 could induce cardiac hypertrophy and dysfunction in mice. Meanwhile, the characteristics of ferroptosis were observed, such as iron homeostasis imbalance, lipid peroxidation, mitochondrial damage and abnormal expression of key molecules. MitoQ treatment could effectively mitigate these alternations. After treating human cardiomyocyte AC16 with PM2.5, ferroptosis activator (Erastin) and inhibitor (Fer-1), it was found that PM2.5 could promote ferritinophagy and lead to lipid peroxidation, mitochondrial dysfunction as well as the accumulation of intracellular and mitochondrial labile iron. Subsequently, mitophagy was activated and provided an additional source of labile iron, enhancing the sensitivity of AC16 cells to ferroptosis. Furthermore, Fer-1 alleviated PM2.5-induced cytotoxicity and iron overload in the cytoplasm and mitochondria of AC16 cells. It was worth noting that during the process of PM2.5 caused ferroptosis, abnormal iron metabolism mediated the activation of ferritinophagy and mitophagy in a temporal order. In addition, NCOA4 knockdown reversed the iron homeostasis imbalance and lipid peroxidation caused by PM2.5, thereby alleviating ferroptosis. In summary, our study found that iron homeostasis imbalance-mediated the crosstalk of ferritinophagy and mitophagy played an important role in PM2.5-induced ferroptosis and cardiac hypertrophy.

The cardioprotective potential of melatonin on cardiac hypertrophy: A mechanistic overview

Cardiac hypertrophy (CH) is an increment of muscle mass to maintain the heart regular operations. A physiological cardiac hypertrophy due to exercise or other normal physiological process is characterized by normal contractile function and structural framework of heart tissue. In contrast, pathological hypertrophy occurs in response to increased pressure or volume overload from several cardiovascular diseases including hypertension, valvular diseases, cardiac infarction and heart failure. It is of major concern as it is one of the leading causes of death worldwide. Despite much progress in this field there is a scope for understanding of the molecular mechanisms of this condition. In this review, various types of cardiac hypertrophy and their intricate physio-pathological mechanisms have been discussed. In addition, the genetic mutations in sarcomere genes and oxidative stress are also closely linked to hypertrophic cardiomyopathy. Although several drugs against cardiac hypertrophy have been used, it appears that melatonin, due to its high bioavailability and low side effects, is a better candidate than the conventional medicine for treatment of hypertrophic cardiomyopathy. Melatonin, a hormone and a potent antioxidant, is secreted mainly from the pineal gland, but it is also synthesized from different peripheral tissues including the heart. This molecule can regulate a myriad of cellular functions.  It can protect against cardiac hypertrophy via reducing oxidative stress, elevating Cu-Mn SOD via controlling several cell signalling pathways of Akt/mTOR, ROR-α and NLRP3 cascades. Melatonin also mitigates cardiac hypertrophy by suppressing pro-inflammatory cytokines including TNF-α and TGF-β and cardiac hypertrophy markers like β-MHC, ANP, BNP, LDH. This review focuses on the molecular mechanisms of cardiac hypertrophy and the defensive role of melatonin on it. We propose melatoninas a propitious adjunct for the treatment of cardiac hypertrophy.

Mitochondria and NLRP3 inflammasome in cardiac hypertrophy.

Cardiac hypertrophy is the main adaptive response of the heart to chronic loads; however, prolonged or excessive hypertrophy promotes myocardial interstitial fibrosis, systolic dysfunction, and cardiomyocyte death, especially aseptic inflammation mediated by NLRP3 inflammasome, which can aggravate ventricular remodeling and myocardial damage, which is an important mechanism for the progression of heart failure. Various cardiac overloads can cause mitochondrial damage. In recent years, the mitochondria have been demonstrated to be involved in the inflammatory response during the development of cardiac hypertrophy in vitro and in vivo. As the NLRP3 inflammasome and mitochondria are regulators of inflammation and cardiac hypertrophy, we explored the potential functions of the NLRP3 inflammasome and mitochondrial dysfunction in cardiac hypertrophy. In particular, we proposed that the induction of mitochondrial dysfunction in cardiomyocytes may promote NLRP3-dependent inflammation during myocardial hypertrophy. Further in-depth studies could prompt valuable discoveries regarding the underlying molecular mechanisms of cardiac hypertrophy, reveal novel anti-inflammatory therapies for cardiac hypertrophy, and provide more desirable therapeutic outcomes for patients with cardiac hypertrophy.

Actin-Binding Proteins in Cardiac Hypertrophy.

The heart reacts to a large number of pathological stimuli through cardiac hypertrophy, which finally can lead to heart failure. However, the molecular mechanisms of cardiac hypertrophy remain elusive. Actin participates in the formation of highly differentiated myofibrils under the regulation of actin-binding proteins (ABPs), which provides a structural basis for the contractile function and morphological change in cardiomyocytes. Previous studies have shown that the functional abnormality of ABPs can contribute to cardiac hypertrophy. Here, we review the function of various actin-binding proteins associated with the development of cardiac hypertrophy, which provides more references for the prevention and treatment of cardiomyopathy.

Abstract P2020: A Novel Molecular Mechanism Of Cardiac Hypertrophy

Proliferation of cardiac myocytes is accompanied by increases in cell mass to maintain myocyte size in fetal heart. In adult cardiac myocytes, cell growth becomes uncoupled from proliferation after growth stimuli, resulting in hypertrophic growth. Both proliferation and hypertrophy growth of cardiac myocytes require more protein synthesis. Brf1 (TF IIB-related factor 1) and Pol III genes (RNA Polymerase III-dependent genes) are the dominant factors of protein produce. Brf1 is a key regulator for Pol III genes. Cardiac hypertrophy is a critical risk factor for cardiovascular disease, including heart failure, arrhythmia, and sudden death. Cardiac hypertrophy involves both the processes of embryonic gene expression and transcriptional reprogramming. The processes are tightly modulated by different signal pathways and epigenetic regulation. Diabetic cardiomyopathy is associated with an increased risk for heart failure and death in patients with diabetes. To explore the molecular mechanism of cardiac hypertrophy, we investigate the alterations of Brf1 and Pol III gene transcription under glucose treatment by using cell culture model and animal model. We have found that glucose increases Brf1 expression and Pol III gene transcription. We identified that these genes are mediated by JNK1, MSK1, pAMPK and phosphorylated histone H3. inhibiting the pathways decrease Brf1 expression, reduce Pol III gene transcription, consequently repression of myocytes growth. It implies that developing an effective inhibitor to repress Brf1 expression may provide a potential approach for the therapy of cardiac hypertrophy. More studies on cardiac hypertrophy are going in our laboratory.

Potential molecular mechanism of cardiac hypertrophy in mice induced by exposure to ambient PM2.5

Cardiac hypertrophy could be induced by ambient fine particulate matter (PM2.5) exposure. Since cardiac hypertrophy represents an early event leading to heart dysfunction, it is necessary to explore the molecular mechanisms, which are largely unknown. In the present study, an ambient particulate matter exposure mice model was established to explore its adverse effects related to the heart and the potential mechanisms. Forty-eight male C57BL/6 mice were randomly subjected to three groups: filtered air group, unfiltered air group and concentrated air group, and were exposed for 8 and 16 weeks, 6 h/day, respectively. In vitro experiments, the cardiac muscle cell line (HL-1) was treated with PM2.5 (0, 25, 50 and 100 μg/mL) for 24 h. In the present study, cardiac hypertrophy was occurred in vivo and vitro after exposure to PM2.5. Mechanistically, circ_0001859 could sponge miR-29b-3p, which could interact with 3′UTRs of Ctnnb1 (gene name of β-catenin). And Ctnnb1 expression was transcriptionally inhibited by si-circ_0001859 or miR-29b-3p mimic in HL-1 cells. Additionally, miR-29b-3p inhibitor could also make a reversion about the inhibition effect of circ_0001859 silencing on Ctnnb1 mRNA level in HL-1 cells. Functionally, knockout of circ_0001859 or overexpression of miR-29b-3p could inhibit LEF1/IGF-2R pathway and alleviate the progress of hypertrophy induced by PM2.5 in HL-1 cells. And miR-29b-3p inhibitor could reverse the inhibition effect of circ_0001859 silencing on hypertrophic response induced by PM2.5 in HL-1 cells. Consequently, the data demonstrated that circRNA_0001859 promoted the process of cardiac hypertrophy through suppressing miR-29b-3p leading to enhance Ctnnb1 level, and activated downstream pathway molecules LEF1/IGF-2R.

Comprehensive Analysis and Co-Expression Network of mRNAs and lncRNAs in Pressure Overload-Induced Heart Failure

Aim: Heart failure (HF) is the end stage of various cardiovascular diseases. However, the precise regulation of gene expression profiles and functional mechanisms of long non-coding RNAs (lncRNAs) in HF remain to be elucidated. The present study aimed to identify the differentially expressed profiles and interaction of messenger RNAs (mRNAs) and lncRNAs in pressure overload-induced HF. Methods: Male Sprague-Dawley rats were randomly divided into the HF group and the sham-operated group. HF was induced by the transverse aortic constriction (TAC) surgery. The cardiac expression profiles of mRNAs and lncRNAs in HF were investigated using the microarray. Bioinformatics analyses and co-expression network construction were performed from the RNA sequencing data. Results: The expression profiles of mRNAs and lncRNAs showed significant differences between HF and controls. A total of 147 mRNAs and 162 lncRNAs were identified to be differentially expressed with a fold change of >2 in HF. The relative expression levels of several selected mRNAs and lncRNAs were validated by quantitative PCR. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that diverse pathways were involved in the molecular mechanisms of cardiac hypertrophy and HF including immune response, smooth muscle contraction, ion transmembrane transport. The mRNA-lncRNA and transcription factors (TFs)-lncRNA co-expression networks were constructed and several genes and TFs were identified as key regulators in the pathogenesis of HF. Further functional prediction showed that the lncRNA NONRATT013999 was predicted to cis-regulate mRNA CDH11, and NONRATT027756 was predicted to trans-regulate HCN4. Conclusion: This study revealed specific expression regulation and potential functions of mRNAs and lncRNAs in pressure overload-induced HF. These results will provide new insights into the underlying mechanisms and potential therapeutic targets for HF.

Cardiac hypertrophy or failure? - A systematic evaluation of the transverse aortic constriction model in C57BL/6NTac and C57BL/6J substrains.

BackgroundThe mouse model of transverse aortic constriction (TAC) has been widely used as a cardiac stress in the investigation of the molecular mechanisms of cardiac hypertrophy. Recently, the International Knockout Mouse Consortium has selected the C57BL/6NTac (BL/6N) mouse strain to generate null alleles for all mouse genes; however, a range of genetic and cardiac phenotypic differences have been reported between this substrain and the commonly used C57BL/6J (BL/6J) substrain. It has been reported by Garcia-Menendez and colleagues that 12-week C57BL/6NTac mice are susceptible to heart failure but little is known about the cardiac remodeling in this substrain as cardiac function progresses from compensation to decompensation.MethodsBL/6J and BL/6N mice were subjected to pressure overload via TAC. The impact of both age and duration of cardiac pressure overload induced by TAC on cardiac remodelling were systematically assessed.ResultsOur data showed that BL/6N mice developed eccentric hypertrophy with age- and time-dependent deterioration in cardiac function, accompanied by considerable interstitial fibrosis. In contrast, BL/6J mice were more resilient to TAC-induced cardiac stress and developed variable cardiac phenotypes independent of age and the duration of pressure overload. This was likely due to the greater variability in pre-TAC aortic arch dimension as measured by echocardiography. In addition to increased expression of brain natriuretic peptide and collagen gene type 1 and 3, BL/6N mice also had greater angiotensin II type 2 receptor (AT2R) gene expression than BL/6J counterparts at baseline and after 2-weeks TAC, which may contribute to the exacerbated interstitial fibrosis.ConclusionsBL/6N and BL/6J mice have very different responses to TAC stimulation and these differences should be taken into consideration when using the substrains to investigate the mechanisms of hypertrophy and heart failure.

Overexpression of miR-135b attenuates pathological cardiac hypertrophy by targeting CACNA1C

BackgroundCardiac hypertrophy is a serious factor underlying heart failure. Although a large number of pathogenic genes have been identified, the underlying molecular mechanisms of cardiac hypertrophy are still poorly understood. MicroRNAs are a class of small non-coding RNAs which regulate their target genes at the post-transcriptional level. L-type calcium channels play important role in hypertrophic signaling pathways, and CACNA1C is encoded by L-type calcium channels. Here, we hypothesize that the overexpression of miR-135b can attenuate hypertrophy by targeting CACNA1C. MethodsWe test the functional involvement of miR-135b in cardiac hypertrophy model. In order to evaluate the effect of miR-135b in cardiac hypertrophy, miR-135b mimic, miR-135b agomir and α-MHC-miR-135b transgenic mice were used for the overexpression of miR-135b. Luciferase reporter assays were used to testify the binding of miR-135b to the CACNA1C 3′UTR. ResultsOur results revealed that in a pathological cardiac hypertrophy model, the expression of miR-135b was clearly downregulated. Hypertrophic marker genes were upregulated after the knockdown of miR-135b in vitro, while the overexpression of miR-135b attenuated hypertrophy. These results suggested that miR-135b may weaken hypertrophic signals. We then explored the mechanism of miR-135b in hypertrophy and identified that CACNA1C was a target gene for miR-135b. The overexpression of miR-135b attenuated cardiac hypertrophy by targeting CACNA1C. ConclusionsOur studies revealed that miR-135b is a critical regulator of cardiomyocyte hypertrophy. Our findings may provide a novel strategy for the treatment of cardiac hypertrophy.

Modeling Human Cardiac Hypertrophy in Stem Cell-Derived Cardiomyocytes.

SummaryCardiac hypertrophy accompanies many forms of cardiovascular diseases. The mechanisms behind the development and regulation of cardiac hypertrophy in the human setting are poorly understood, which can be partially attributed to the lack of a human cardiomyocyte-based preclinical test system recapitulating features of diseased myocardium. The objective of our study is to determine whether human embryonic stem cell-derived cardiomyocytes (hESC-CMs) subjected to mechanical stretch can be used as an adequate in vitro model for studying molecular mechanisms of cardiac hypertrophy. We show that hESC-CMs subjected to cyclic stretch, which mimics mechanical overload, exhibit essential features of a hypertrophic state on structural, functional, and gene expression levels. The presented hESC-CM stretch approach provides insight into molecular mechanisms behind mechanotransduction and cardiac hypertrophy and lays groundwork for the development of pharmacological approaches as well as for discovering potential circulating biomarkers of cardiac dysfunction.

Astragaloside IV protects against the pathological cardiac hypertrophy in mice

Although pathologic hypertrophic hearts currently maintain output, sustained cardiac hypertrophy could predispose a patient to arrhythmia and sudden death, and also cause heart failure. Thus, finding effective treatment and exploring the underlying molecular mechanisms of cardiac hypertrophy is urgently necessary. Astragaloside IV (AST-IV) is the main active component, extracted from the traditional Chinese medicinal herb Astragalus membranaceus. Previous studies have indicated that AST-IV has various bioactivities, such as anti-cancer, anti-oxidative stress and anti-inflammation. In the present study, we aimed to explore the effects of AST-IV on cardiac hypertrophy induced by aortic banding (AB) surgery in mice, and to reveal the underlying signaling mechanisms. The suppressor of IKKε (SIKE) is a negative regulator of the interferon pathway, which could be enhanced by AST-IV to ameliorate pathological cardiac hypertrophy in mice through inactivating TANK-binding kinase 1 (TBK1)/PI3K/AKT signaling pathway. AST-IV attenuated cardiac hypertrophy, collagen accumulation and abnormal cardiac functions. In addition, AB-induced apoptosis and inflammation in the heart tissue samples of mice, which were attenuated by AST-IV administration through inhibiting SIKE expression levels. Together, the findings above indicated that AST-IV might be a potential candidate to prevent cardiac hypertrophy via elevating SIKE to suppress TBK1/PI3K/AKT activity.

RETRACTED: Association of angiotensin II receptor 1 and lectin-like oxidized low-density lipoprotein receptor-1 mediates the cardiac hypertrophy induced by oxidized low-density lipoprotein

To date the molecular mechanism of cardiac hypertrophy has not been completely elucidated. Since oxidized low-density lipoprotein (ox-LDL) is considered a risk marker for early ventricular remodeling, we speculated that ox-LDL may be related to cardiac hypertrophy. We observed the significantly upregulation of plasma ox-LDL and hypertrophic responses, such as cardiomyocyte size and specific gene expressions in Apo E-/- mice fed with high fat diet, accompanied by the upregulation of AT1-R and lectin-like oxidized low-density protein receptor 1 (LOX-1). Ox-LDL treatment with neonatal rat cardiomyocyte for 24h significantly induced similar hypertrophic responses and also upregulation of AT1-R and LOX-1. The analysis of co-immunoprecipitation and the bimolecular fluorescence complementation assay proved that LOX-1 and AT1-R could directly bind together in the presence of ox-LDL, suggesting a critical role of the association between LOX-1 and AT1-R in ox-LDL-induced cardiac hypertrophy. Furthermore, we found that the AT1-R blocker Losartan and LOX-1 neutralizing antibody through inhibiting AT1-R or LOX-1 could both decline ox-LDL-induced hypertrophic responses whereas angiotensin converting enzyme inhibitor Enalapril only partially inhibited the responses stimulated by ox-LDL. These findings suggested that ox-LDL could induce cardiac hypertrophy through the direct association of AT1-R and LOX-1.

Let-7a Is an Antihypertrophic Regulator in the Heart via Targeting Calmodulin.

Background: MicroRNAs (miRNAs) have been emerged as important regulator in a multiple of cardiovascular disease, including arrhythmia, cardiac hypertrophy and fibrosis, and myocardial infarction. The aim of this study was to investigate whether miRNA let-7a has antihypertrophic effects in angiotensin II (AngII)-induced cardiac hypertrophy.Methods: Neonatal rat ventricular myocytes (NRVMs) were exposed to AngII for 36 h as a cellular model of hypertrophy; subcutaneous injection of AngII for 2 weeks was used to establish a mouse model of cardiac hypertrophy in vivo study. Cell surface area (CSA) was measured by immunofluorescence cytochemistry; expression of hypertrophy-related genes ANP, BNP, β-MHC was detected by Real-time PCR; luciferase activity assay was performed to confirm the miRNA's binding site in the calmodulin (CaM) gene; CaM protein was detected by Western blot; the hypertrophy parameters were measured by echocardiographic assessment.Results: The expression of let-7a was decreased in AngII-induced cardiac hypertrophy in vitro and in vivo. Overexpression of let-7a attenuated AngII-induced increase of cell surface area and repressed the increased mRNA levels of ANP, BNP and β-MHC. Dual-luciferase reporter assay showed that let-7a could bind to the 3'UTR of CaM 1 gene. Let-7a downregulated the expression of CaM protein. In vivo, let-7a produced inhibitory effects on cardiac hypertrophy, including the downregulation of cross-sectional area of cardiomyocytes in mouse heart, the reduction of IVSD and LVPWD, the suppression of hypertrophy marker genes ANP, BNP, β-MHC mRNA level, and the downregulation of CaM protein level.Conclusions: let-7a possesses a prominent anti-hypertrophic property by targeting CaM genes. The findings provide new insight into molecular mechanism of cardiac hypertrophy.

The mechanosensitive APJ internalization via clathrin-mediated endocytosis: A new molecular mechanism of cardiac hypertrophy

The G protein-coupled receptor APJ elicits cellular response to diverse extracellular stimulus. Accumulating evidence reveals that APJ receptor plays a prominent role in the cardiomyocyte adapting to hypertrophic stimulation. At present, it remains obscure that the regulatory mechanism of APJ receptor in myocardial hypertrophy. The natural endogenous ligands apelin and Elabela as well as agonists maintain high affinity for the APJ receptor and drive its internalization. Ligand-activated receptor internalization is mainly performed by clathrin-mediated endocytic pathway. Simultaneously, clathrin-mediated endocytosis takes participate in the occurrence and development of cardiac hypertrophy. In this study, we hypothesize that natural ligands and agonists induce the mechanosensitive APJ internalization via clathrin-mediated endocytosis. APJ internalization may contribute to the development of cardiac hypertrophy. The mechanosensitive APJ internalization via clathrin-mediated endocytosis may be a new molecular mechanism of cardiac hypertrophy.

MicroRNA-22 Regulates Cardiac Hypertrophy and Remodeling in Response to Stress

The adult heart is composed primarily of terminally differentiated, mature cardiomyocytes that express signature genes related to contraction. In response to mechanical or pathological stress, the heart undergoes hypertrophic growth, a process defined as an increase in cardiomyocyte cell size without an increase in cell number. However, the molecular mechanism of cardiac hypertrophy is not fully understood. To identify and characterize microRNAs that regulate cardiac hypertrophy and remodeling. Screening for muscle-expressed microRNAs that are dynamically regulated during muscle differentiation and hypertrophy identified microRNA-22 (miR-22) as a cardiac- and skeletal muscle-enriched microRNA that is upregulated during myocyte differentiation and cardiomyocyte hypertrophy. Overexpression of miR-22 was sufficient to induce cardiomyocyte hypertrophy. We generated mouse models with global and cardiac-specific miR-22 deletion, and we found that cardiac miR-22 was essential for hypertrophic cardiac growth in response to stress. miR-22-null hearts blunted cardiac hypertrophy and cardiac remodeling in response to 2 independent stressors: isoproterenol infusion and an activated calcineurin transgene. Loss of miR-22 sensitized mice to the development of dilated cardiomyopathy under stress conditions. We identified Sirt1 and Hdac4 as miR-22 targets in the heart. Our studies uncover miR-22 as a critical regulator of cardiomyocyte hypertrophy and cardiac remodeling.

Duke/UNC to helm the JCI in March 2012

As the JCI went to press, ASCI members were returning their ballots to confirm Howard Rockman of Duke University as the next Editor in Chief of the JCI. Rockman will serve as Editor from March 2012 through February 2017 together with an Editorial Board based at Duke, the University of North Carolina, and Duke-NUS Graduate Medical School Singapore. Rockman has studied molecular mechanisms of cardiac hypertrophy and heart failure, concentrating on the regulation of G protein–coupled receptors and their downstream signaling pathways. The JCI recently sat down with Rockman to discuss his visions for the journal. JCI: Why do you think Duke and UNC are the right place to house the JCI? Rockman: The scientists at Duke and UNC are really outstanding. I’ve spent a lot of time speaking with the proposed Editors, and they’re ready for it. They’re energetic, they’re committed, and they’re excellent scientists. JCI: Who are some of the people you have assembled to help you in this endeavor? Rockman: In addition to a strong team of Deputy and Associate Editors, I have asked Bob Lefkowitz to chair a newly created Executive Council. This council will be responsible for evaluating our progress year to year, and providing editorial advice on papers that need additional review — like when an author feels like they haven’t had a fair review. He’ll also be in charge of working with us to determine if there’s been any scientific malfeasance or breaches of scientific integrity. The other senior member of the board will be David Virshup, from Duke-NUS Singapore. He’s going to be our Asia Editor — we’ll be looking to him to help us attract the best science in Asia that we might not already be getting. The Deputy Editors will be Tom Coffman and Paul Noble of Duke and Norman Sharpless from UNC. They are outstanding scientists and I’m going to lean on them heavily for their advice and scientific knowledge, and of course for their sense of humor. JCI: You cannot undervalue the need for comic relief in this job. Rockman: Humor is a wonderful form of creativity, and Dr. Noble in particular is very good at getting us to laugh. You know, when you’re this busy and working this hard, humor is really important. JCI: What sort of papers do you want to encourage people to send in? Rockman: What we want are papers that use basic science critical thinking, cellular systems, and tractable genetic models to identify new biological mechanisms that can be translated to better understand or treat a disease. It is also the Journal of Clinical Investigation, and I’d like to see more studies in humans. The paper I’d like to see is one where there are human studies, but the authors went back into a cellular or other model systems to understand the mechanism. JCI: The JCI has recently joined 2011, and we have both a Facebook page and a Twitter feed. Do you think you’re going to be actively tweeting as JCI Editor? Rockman: I’m going to have to learn how to do that! During the application process, my son Michael went onto the JCI Facebook page and asked if he should join. Apparently he was number 99. The way I like to get my information is so different from the way the younger generation does. I was recently sitting at the table after dinner reading the New York Times — I love the print; I love the smell of the paper and getting the ink on my fingers. Michael sat down at the table after dinner and was looking at his iPhone, and I looked up and in a somewhat scornful way and said, “Instead of playing games on your phone, why don’t you pick up the paper?” And he turned the phone to me and he was reading David Brooks. And he said, “Dad, I’m reading today’s news. You’re reading yesterday’s news.” Everyone gets their information in different ways. His generation wants to interact with media, not simply be passive, and I think we have to be responsive to a diverse constituency. Today people get their information in many ways. They don’t just pick up a journal and thumb through it. The way for us to really get our message across and have our scientific discoveries read is to use all the available technology to enhance the experience. JCI: What sort of things do you envision changing or adding to the front half of the JCI and online? Rockman: Together with embracing new media, I want to look for different ways to tell the story of science. I would like to have podcasts linked to some articles, wherein we could interview senior authors and allow them to tell the story of their paper. It could almost be like you were sitting in a seminar and listening to them. I’d also like to bring back into the JCI the legends in science: I have the idea to add a “Conversation with Giants” section wherein a new ASCI member could interview a legend in the field and get a sense of what it was like for them to be in science — their thrill of discovery. The other article type I’d like to add is one where we explore a translational link between a paper that we publish and how it affects our health. These articles could explore how the basic science could affect our health and how we treat patients of a certain disease. JCI: Any parting words about the intellectual stewardship of the JCI? Rockman: I believe the JCI editorship is not a trophy, but a responsibility. Moreover, this is not my JCI, but our JCI. I think the journal should publish the best in biomedical science by generating new knowledge that advances our understanding of the biology of disease and leads to therapeutic advances. After reading a JCI paper, I want our readers to sit back and say “Wow, what an amazing discovery — what a beautiful story.”

Taking pressure off the heart: the ins and outs of atrophic remodelling

Our work on atrophic remodelling of the heart has led us to appreciate the simple principles in biology: (i) the dynamic nature of intracellular protein turnover, (ii) the return to the foetal gene programme when the heart remodels, and (iii) the adaptive changes of cardiac metabolism. Although the molecular mechanisms of cardiac hypertrophy are many, much less is known regarding the molecular mechanisms of cardiac atrophy. We state the case that knowing more about mechanisms of atrophic remodelling may provide insights into cellular consequences of metabolic and haemodynamic unloading of the stressed heart. Overall we strive to find an answer to the question: 'What makes the failing heart shrink and become stronger?' We speculate that signals arising from intermediary metabolism of energy-providing substrates are likely candidates.

Novel regulators and drug targets of cardiac hypertrophy

Cardiac hypertrophy is classically considered as an adaptive and compensatory response enabling cardiomyocytes to increase their work output and thus cardiac function. Biomechanical stress and neurohumoral activation are the most important triggers of pathological hypertrophy and the transition of cardiac hypertrophy to heart failure. Several novel regulators and putative drug targets of cardiac hypertrophy have been found by using gene-modified and acquired models of cardiac hypertrophy. Recent studies have also revealed distinct patterns of cardiac substrate utilization in cardiac hypertrophy and heart failure. The use of novel systems biology techniques such as metabolomics may therefore in future provide insights into the metabolic processes and cardiovascular biology related to cardiac hypertrophy and also extend the ability to discover circulating biomarkers for cardiovascular diseases. The present review discusses current knowledge on molecular mechanisms of cardiac hypertrophy, with special emphasis on novel regulators and putative drug targets of cardiac hypertrophy such as the tissue renin-angiotensin-aldosterone system, calcineurin/nuclear factor of activated T cells pathway, phosphatidylinositol 3-kinase/growth promoting protein kinase B, mammalian target of rapamycin, histone deacetylases, AMPkinases, microRNAs and angiogenetic factors.

The effects of intra-cage aspen tube on cardiac morphology and gene expression

According to the European recommendations rodents should be provided with a nest box if there is insufficient nesting material to build a complete, covered nest. Rats are generally poor nest builders; hence an additional structure is needed. Optimally, housing refinement may be combined with better science; at least it should not detract from the scientific integrity. In order to evaluate these options, there is a need to assess the items used in individual research projects. Studies investigating molecular mechanisms of cardiac hypertrophy and heart failure are typically long-lasting studies; therefore, refinement of the housing of rats in these studies is important. The aim of this study was to evaluate in rats whether a wooden tube has any impact on cardiac morphology or on basal gene expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP); known markers of cardiac overload, hypertrophy and heart failure. The experimental protocol simulated cardiovascular studies, but without any surgical operations. A total of 42 male Hsd:SD rats were used in an eight-week experiment. After weaning, the experimental group was provided with a rectangular aspen tube and nesting material, and the control group with only nesting material. ANP and BNP gene expression were measured from the left ventricles with Northern blot analysis postmortem along with the absolute weights of the whole heart, left and right atria and left and right chambers. The weights of the whole heart and left chamber were also analysed in relation to body weight. No statistically significant differences were observed in any of these variables. The inter-individual variation was also unchanged by the cage item. In conclusion, the aspen tube does not disrupt research results or alter the number of animals needed and can therefore be recommended for enrichment purposes in cardiovascular studies.