Abstract 084: Dkk1 Knock out Leads To Augmentation Of Cardiac Hypertrophy Following Aortic Banding

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Johannes H Riffel ◽  
Elmar Bernhold ◽  
Marco Hagenmueller ◽  
Min Zhang ◽  
Christof Niehrs ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Wnt Signaling ◽  
Histological Evaluation ◽  
Heart Weight ◽  
Sham Operation ◽  
Aortic Banding ◽  
Knock Out ◽  
Hypertrophic Growth ◽  
Knock Out Mice

Background: Myocardial hypertrophy is an important risk factor for cardiac morbidity and mortality. In the normal adult heart, Wnt signaling remains quiescent. However, recent studies have demonstrated reactivation of Wnt signaling in hypertrophic growth of cardiomyocytes. Under such conditions Wnt signaling may be beneficial or maladaptive depending on the context. The Wnt coreceptors LRP5 and LRP6 are important for signal transmission via the β-catenin pathway and are negatively regulated by Dkk1, a member of a small family of secretory proteins. Dkk1 binds to LRP6 and thereby acts as a Wnt antagonist. In our study we investigated the cardiovascular phenotype of Dkk1 knock-out mice following aortic banding. Study Design and Results: Dkk1 (+/-) knock-out mice were subjected to aortic banding (AB) or sham operation. After 4 weeks echocardiographic and invasive measurements were performed. After that the mice were euthanized, heart weight was measured and myocardial samples were snap frozen for biochemical measurements or fixed in formalin for further histological evaluation. Under baseline conditions there were no differences in cardiomyocyte size, heart weight and cardiac function in Dkk1 knock-out animals compared to wild type animals. 4 weeks after aortic banding we observed a significant increase in heart weight/body weight ratio in Dkk1 knock out animals compared to the control group (7.3 ± 0.3 mg/g vs. 6.4 ± 0.3 mg/g, p < 0.05). Furthermore cardiomyocyte size was highly elevated in Dkk1 knock out mice compared to control animals, suggesting an augmentation in cardiac hypertrophy. Transcription levels of the pro-hypertrophic markers atrial natriuretic factor (ANF) and beta-MHC were increased in Dkk1 knock out animals. Interestingly echocardiographic data revealed an aggravation of cardiac function in Dkk1 knock out mice following aortic banding (Ejection fraction (EF): 62 ± 3 % vs. 74 ± 1 %, p < 0.05). Summary: Our findings suggest that Dkk1 knock out aggravates cardiac hypertrophy following aortic banding. The underlying molecular mechanisms remain to be further explored.

Abstract 20118: Defining the Sufficiency of Atg7 to Suppress Phenylephrine-induced Cardiac Hypertrophy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Marcus Tjeerdsma ◽  
Levi Froke ◽  
Jessica Freeling ◽  
Scott Pattison
Keyword(s):  
Body Weight ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Heart Weight ◽  
Autophagic Flux ◽  
Specific Expression ◽  
Hypertrophic Growth ◽  
Fractional Shortening

Introduction: Macroautophagy is a process of bulk protein degradation. Our prior work showed that Atg7 expression is sufficient to induce autophagic flux in vitro and in vivo . When Atg7 was co-expressed with CryAB R120G in the heart, cardiac hypertrophy was blunted in heart weight/body weight ratios and fetal gene expression markers. To determine if Atg7 expression is sufficient to limit hypertrophic growth in another model, we tested the effects of Atg7 overexpression with phenylephrine-induced hypertrophy both in vitro and in vivo . Hypothesis: Atg7 will blunt the hypertrophic effects of phenylephrine. Methods: Rat neonatal cardiomyocytes were infected with adenoviruses expressing either LacZ or Atg7 and treated with phenylephrine to induce cardiomyocytes hypertrophy. Osmotic pumps were surgically implanted into control mice and mice with cardiac-specific expression of Atg7 to infuse phenylephrine (PE) or vehicle (saline) for four weeks. Results: PE treatment significantly increased neonatal cardiomyocyte areas in LacZ-expressing cells, while Atg7-expressing cardiomyocytes showed no growth. In mice, all genotypes responded to PE treatment with significantly increased heart weight/body weight ratios and increased fiber size. However, Atg7-expressing hearts differed significantly from control hearts in normalized heart mass following PE delivery. Vehicle treated Atg7-expressing hearts had 17% smaller myofiber cross-sectional areas than those from control genotypes and had a reduced hypertrophic response to PE, relative to controls. Echocardiography showed that Atg7-expressing hearts had significantly elevated cardiac function (% fractional shortening) prior to and throughout the experiment over control hearts (33% vs. 29%). PE significantly increased fractional shortening) from 29% to 36% in control hearts, but failed to significantly elevate cardiac function in Atg7-expressing hearts further (33% vs 35%). Additional assays are underway to understand the Atg7-dependent adaptations to PE. Conclusion: Atg7 expression yields modestly smaller hearts with enhanced cardiac function which may protect them from hypertrophic stresses like phenylephrine.

Blockade of MyD88 attenuates cardiac hypertrophy and decreases cardiac myocyte apoptosis in pressure overload-induced cardiac hypertrophy in vivo

2006 ◽  
Vol 290 (3) ◽  
pp. H985-H994 ◽  
Author(s):  
Tuanzhu Ha ◽  
Fang Hua ◽  
Yuehua Li ◽  
Jing Ma ◽  
Xiang Gao ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Cardiac Myocyte ◽  
Pressure Overload ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Heart Weight ◽  
Aortic Banding ◽  
Myocyte Apoptosis ◽  
Cardiac Myocyte Apoptosis

In this study, we evaluated whether blocking myeloid differentiation factor-88 (MyD88) could decrease cardiac myocyte apoptosis following pressure overload. Adenovirus expressing dominant negative MyD88 (Ad5-dnMyD88) or Ad5-green fluorescent protein (GFP) (Ad5-GFP) was transfected into rat hearts ( n = 8/group) immediately followed by aortic banding for 3 wk. One group of rats ( n = 8) was subjected to aortic banding for 3 wk without transfection. Sham surgical operation ( n = 8) served as control. The ratios of heart weight to body weight (HW/BW) and heart weight to tibia length (HW/TL) were calculated. Cardiomyocyte size was examined by FITC-labeled wheat germ agglutinin staining of membranes. Cardiac myocyte apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, and myocardial interstitial fibrosis was examined by Masson's Trichrome staining. Aortic banding significantly increased the HW/BW by 41.0% (0.44 ± 0.013 vs. 0.31 ± 0.008), HW/TL by 47.2% (42.7 ± 1.30 vs. 29.0 ± 0.69), cardiac myocyte size by 49.6%, and cardiac myocyte apoptosis by 11.5%, and myocardial fibrosis and decreased cardiac function compared with sham controls. Transfection of Ad5-dnMyD88 significantly reduced the HW/BW by 18.2% (0.36 ± 0.006 vs. 0.44 ± 0.013) and HW/TL by 22.3% (33.2 ± 0.95 vs. 42.7 ± 1.30) and decreased cardiomyocyte size by 56.8%, cardiac myocyte apoptosis by 76.2%, as well as fibrosis, and improved cardiac function compared with aortic-banded group. Our results suggest that MyD88 is an important component in the Toll-like receptor-4-mediated nuclear factor-κB activation pathway that contributes to the development of cardiac hypertrophy. Blockade of MyD88 significantly reduced cardiac hypertrophy, cardiac myocyte apoptosis, and improved cardiac function in vivo.

Abstract 47: Loss of the Cardio Protection Inferred by S-nitrosylation of GRK2 At Cysteine 340 Leads to Decreased Cardiac Performance and a Hypertensive Phenotype With Aging

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Christopher J Traynham ◽  
Ancai Yuan ◽  
Erhe Gao ◽  
Walter Koch
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Ischemia Reperfusion ◽  
Cardiac Performance ◽  
Heart Weight ◽  
Cardiac Phenotype ◽  
Cardio Protection ◽  
G Protein Coupled ◽  
Global Population

In the next 35 years, the global population of individuals above 60 years of age will double to approximately 2 billion. In the aged population, cardiovascular diseases are known to occur at a higher prevalence ultimately leading to increased mortality. G protein-coupled receptors (GPCRs) have been identified as vital regulators of cardiac function. GPCR kinases (GRKs) are important in cardiac GPCR regulation through desensitization of these receptors. GRK2 is highly expressed in the heart, and has been widely characterized due to its upregulation in heart failure. Studies from our lab have shown that elevated GRK2 levels in ischemia-reperfusion (I/R) injury result in a pro-death phenotype. Interestingly, cardio-protection can be inferred via S-nitrosylation of GRK2 at cysteine 340. Further, we have generated a knock-in GRK2 340S mouse, in which cysteine 340 was mutated to block dynamic GRK2 S-nitrosylation. GRK2 340S mice are more susceptible to I/R injury. Given that GRK2 340S mice are more susceptible to oxidative stress, and there is a nitroso-redox imbalance in senescence, it is possible that these mice are more likely to exhibit decreased cardiac performance as they age. Therefore, we hypothesize that with age GRK2 340S knockin mice will develop an overall worsened cardiac phenotype compared to control wild-type (WT) mice. To test this hypothesis, 340S and WT mice were aged for a year, and cardiac function was evaluated via echocardiography. Aged 340S mice exhibited significantly decreased ejection fraction and fraction shortening relative to aged WT controls. Prior to tissue harvesting, in-vivo hemodynamics was conducted via Millar catheterization. At baseline, aged 340S mice exhibited increased systolic blood pressure compared to aged WT mice. At the conclusion of this protocol, mice were sacrificed and heart weight (HW), body weight (BW), and tibia length (TL) measured to evaluate cardiac hypertrophy. Aged 340S mice exhibited significantly increased HW/BW and HW/TL ratios, indicative of cardiac hypertrophy, relative to aged WT controls. Taken together, these data suggest that with age, loss of the cardio protection inferred by S-nitrosylation of GRK2 at leads to decreased cardiac performance, and an overall worsened cardiac phenotype.

Abstract 182: CTRP9 - A Novel Cardiac Derived Secreted Factor With Anti-hypertrophic Properties

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Astrid H Breitbart ◽  
Florian Brandes ◽  
Oliver Müller ◽  
Natali Froese ◽  
Mortimer Korf-Klingebiel ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Real Time ◽  
Real Time Pcr ◽  
Weight Ratio ◽  
Neonatal Rat ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Quantitative Real Time Pcr ◽  
Rat Cardiomyocytes ◽  
Knock Out

Background: CTRP9 (also called C1qtnf9) is a newly discovered secreted protein and a paralog of adiponectin. The biological functions of CTRP9, however, are still largely unknown. Results: Although previous data from a semi-quantitative real-time PCR had suggested that CTRP9 is mainly secreted by adipose tissue, we found its mRNA to be predominantly expressed in the heart by quantitative real-time PCR. Interestingly, we identified CTRP9 mRNA as significantly upregulated in hypertrophied mouse hearts (after 2 weeks of aortic constriction, TAC) as well as in hypertrophied human hearts (24±4-fold versus healthy human myocardium; p<0.01). LacZ staining in myocardial sections of C1qtnf9 tm1(KOMP)Vlcg mice (knock-out for CTRP9, containing a lacZ cassette to replace exon 1-3 of the gene) revealed exclusive expression of CTRP9 in capillary and venous endothelial cells. Adenoviral overexpression of CTRP9 or recombinant CTRP9 strongly inhibited cardiomyocyte hypertrophy (assessed as cell size, protein/DNA-ratio, expression of skeletal α-actin) after stimulation with phenylephrine (PE). Accordingly, myocardial overexpression of CTRP9 via a cardioselective adeno-associated virus (AAV9-CTRP9) in mice dramatically reduced cardiac hypertrophy after two weeks of pressure overload (heart weight/body weight ratio, HW/BW in mg/g: AAV9-control 6.5±0.2 versus AAV9-CTRP9 5.6±0.2; p<0.01). In turn, downregulation of CTRP9 by a specific siRNA aggravated cardiomyocyte growth in response to PE in vitro and CTRP9 knock-out (KO) mice exerted an enhanced hypertrophic response after two weeks of TAC in vivo (% increase in HW/BW versus sham: wild-type 77±13, KO 106±9; p<0.05). Mechanistically, we found that CTRP9 binds to the adiponectin receptor 1 (AdipoR1) and inhibits prohypertrophic mTOR signalling in cardiac myocytes. SiRNA mediated downregulation of AdipoR1 or mTOR in neonatal rat cardiomyocytes abolished the anti-hypertrophic effect of CTRP9. Conclusion: Endothelial cell derived CTRP9 inhibits cardiac hypertrophy through binding to AdipoR1 and inhibition of the mTOR pathway in cardiomyocytes. Therefore, myocardial application of CTRP9 could be a novel strategy to combat pathological cardiac hypertrophy.

scholarly journals Intercalated disc protein Xinβ is required for Hippo-YAP signaling in the heart

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Haipeng Guo ◽  
Yao Wei Lu ◽  
Zhiqiang Lin ◽  
Zhan-Peng Huang ◽  
Jianming Liu ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Cardiac Function ◽  
Heart Development ◽  
Genetic Interaction ◽  
Specific Cell ◽  
Cardiomyocyte Proliferation ◽  
Intercalated Disc ◽  
Knock Out ◽  
Genes Encoding ◽  
Knock Out Mice

Abstract Intercalated discs (ICD), specific cell-to-cell contacts that connect adjacent cardiomyocytes, ensure mechanical and electrochemical coupling during contraction of the heart. Mutations in genes encoding ICD components are linked to cardiovascular diseases. Here, we show that loss of Xinβ, a newly-identified component of ICDs, results in cardiomyocyte proliferation defects and cardiomyopathy. We uncovered a role for Xinβ in signaling via the Hippo-YAP pathway by recruiting NF2 to the ICD to modulate cardiac function. In Xinβ mutant hearts levels of phosphorylated NF2 are substantially reduced, suggesting an impairment of Hippo-YAP signaling. Cardiac-specific overexpression of YAP rescues cardiac defects in Xinβ knock-out mice—indicating a functional and genetic interaction between Xinβ and YAP. Our study reveals a molecular mechanism by which cardiac-expressed intercalated disc protein Xinβ modulates Hippo-YAP signaling to control heart development and cardiac function in a tissue specific manner. Consequently, this pathway may represent a therapeutic target for the treatment of cardiovascular diseases.

scholarly journals The Impact of a Non-Functional Thyroid Receptor Beta upon Triiodotironine-Induced Cardiac Hypertrophy in Mice

2015 ◽  
Vol 37 (2) ◽  
pp. 477-490 ◽  
Author(s):  
Güínever Eustáquio do Império ◽  
Isalira Peroba Ramos ◽  
Letícia Aragão Santiago ◽  
Guilherme Faria Pereira ◽  
Norma Aparecida dos Santos Almeida ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Hormone Receptors ◽  
Heart Function ◽  
Hypertrophic Growth ◽  
Regulation Mechanisms ◽  
Heart Functions ◽  
The Impact

Background/Aims: Thyroid hormone (TH) signalling is critical for heart function. The heart expresses thyroid hormone receptors (THRs); THRα1 and THRβ1. We aimed to investigate the regulation mechanisms of the THRβ isoform, its association with gene expression changes and implications for cardiac function. Methods: The experiments were performed using adult male mice expressing TRβΔ337T, which contains the Δ337T mutation of the human THRB gene and impairs ligand binding. Cardiac function and RNA expression were studied after hypo-or hyperthyroidism inductions. T3-induced cardiac hypertrophy was not observed in TRβΔ337T mice, showing the fundamental role of THRβ in cardiac hypertrophy. Results: We identified a group of independently regulated THRβ genes, which includes Adrb2, Myh7 and Hcn2 that were normally regulated by T3 in the TRβΔ337T group. However, Adrb1, Myh6 and Atp2a2 were regulated via THRβ. The TRβΔ337T mice exhibited a contractile deficit, decreased ejection fraction and stroke volume, as assessed by echocardiography. In our model, miR-208a and miR-199a may contribute to THRβ-mediated cardiac hypertrophy, as indicated by the absence of T3-regulated ventricular expression in TRβΔ337T mice. Conclusion: THRβ has important role in the regulation of specific mRNA and miRNA in T3-induced cardiac hypertrophic growth and in the alteration of heart functions.

scholarly journals Calhex231 Ameliorates Cardiac Hypertrophy by Inhibiting Cellular Autophagy in Vivo and in Vitro

2015 ◽  
Vol 36 (4) ◽  
pp. 1597-1612 ◽  
Author(s):  
Lei Liu ◽  
Chao Wang ◽  
Dianjun Sun ◽  
Shuangquan Jiang ◽  
Hong Li ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cardiac Hypertrophy ◽  
Intracellular Calcium ◽  
Calcium Concentration ◽  
Intracellular Calcium Concentration ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Sham Operation ◽  
Ang Ii

Background/Aims: Intracellular calcium concentration ([Ca2+]i) homeostasis, an initial factor of cardiac hypertrophy, is regulated by the calcium-sensing receptor (CaSR) and is associated with the formation of autolysosomes. The aim of this study was to investigate the role of Calhex231, a CaSR inhibitor, on the hypertrophic response via autophagy modulation. Methods: Cardiac hypertrophy was induced by transverse aortic constriction (TAC) in 40 male Wistar rats, while 10 rats underwent a sham operation and served as controls. Cardiac function was monitored by transthoracic echocardiography, and the hypertrophy index was calculated. Cardiac tissue was stained with hematoxylin and eosin (H&E) or Masson's trichrome reagent and examined by transmission electron microscopy. An angiotensin II (Ang II)-induced cardiomyocyte hypertrophy model was established and used to test the involvement of active molecules. Intracellular calcium concentration ([Ca2+]i) was determined by the introduction of Fluo-4/AM dye followed by confocal microscopy. The expression of various active proteins was analyzed by western blot. Results: The rats with TAC-induced hypertrophy had an increased heart size, ratio of heart weight to body weight, myocardial fibrosis, and CaSR and autophagy levels, which were suppressed by Calhex231. Experimental results using Ang II-induced hypertrophic cardiomyocytes confirmed that Calhex231 suppressed CaSR expression and downregulated autophagy by inhibiting the Ca2+/calmodulin-dependent-protein kinase-kinase-β (CaMKKβ)- AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway to ameliorate cardiomyocyte hypertrophy. Conclusions: Calhex231 ameliorates myocardial hypertrophy induced by pressure-overload or Ang II via inhibiting CaSR expression and autophagy. Our results may support the notion that Calhex231 can become a new therapeutic agent for the treatment of cardiac hypertrophy.

NF-κB activation is required for the development of cardiac hypertrophy in vivo

2004 ◽  
Vol 287 (4) ◽  
pp. H1712-H1720 ◽  
Author(s):  
Yuehua Li ◽  
Tuanzhu Ha ◽  
Xiang Gao ◽  
Jim Kelley ◽  
David L. Williams ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Weight Ratio ◽  
Dominant Negative ◽  
Heart Weight ◽  
Dominant Negative Mutant ◽  
Body Weight Ratio ◽  
Aortic Banding ◽  
Important Target

In the present study, we examined whether NF-κB activation is required for cardiac hypertrophy in vivo. Cardiac hypertrophy in rats was induced by aortic banding for 1, 3, and 5 days and 1–6 wk, and age-matched sham-operated rats served as controls. In a separate group of rats, an IκB-α dominant negative mutant (IκB-αM), a superrepressor of NF-κB activation, or pyrrolidinedithiocarbamate (PDTC), an antioxidant that can inhibit NF-κB activation, was administered to aortic-banded rats for 3 wk. The heart weight-to-body weight ratio was significantly increased at 5 days after aortic banding, peaked at 4 wk, and remained elevated at 6 wk compared with age-matched sham controls. Atrial natriuretic peptide and brain natriuretic peptide mRNA expressions were significantly increased after 1 wk of aortic banding, reached a maximum between 2 and 3 wk, and remained increased at 6 wk compared with age-matched sham controls. NF-κB activity was significantly increased at 1 day, reached a peak at 3 wk, and remained elevated at 6 wk, and IKK-β activity was significantly increased at 1 day, peaked at 5 days, and then decreased but remained elevated at 6 wk after aortic banding compared with age-matched sham controls. Inhibiting NF-κB activation in vivo by cardiac transfection of IκB-αM or by PDTC treatment significantly attenuated the development of cardiac hypertrophy in vivo with a concomitant decrease in NF-κB activity. Our results suggest that NF-κB activation is required for the development of cardiac hypertrophy in vivo and that NF-κB could be an important target for inhibiting the development of cardiac hypertrophy in vivo.

scholarly journals Elevated myocardial Na+/H+ exchanger isoform 1 activity elicits gene expression that leads to cardiac hypertrophy

2010 ◽  
Vol 42 (3) ◽  
pp. 374-383 ◽  
Author(s):  
Jin Xue ◽  
Fatima Mraiche ◽  
Dan Zhou ◽  
Morris Karmazyn ◽  
Tatsujiro Oka ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Interstitial Fibrosis ◽  
Gene Activation ◽  
Weight Ratio ◽  
Heart Weight ◽  
Peroxisome Proliferator ◽  
Cross Sectional

In myocardial disease, elevated expression and activity of Na+/H+ exchanger isoform 1 (NHE1) are detrimental. To better understand the involvement of NHE1, transgenic mice with elevated heart-specific NHE1 expression were studied. N-line mice expressed wild-type NHE1, and K-line mice expressed activated NHE1. Cardiac morphology, interstitial fibrosis, and cardiac function were examined by histological staining and echocardiography. Differences in gene expression between the N-line or K-line and nontransgenic littermates were probed with genechip analysis. We found that NHE1 K-line (but not N-line) hearts developed hypertrophy, including elevated heart weight-to-body weight ratio and increased cross-sectional area of the cardiomyocytes, interstitial fibrosis, as well as depressed cardiac function. N-line hearts had modest changes in gene expression (50 upregulations and 99 downregulations, P < 0.05), whereas K-line hearts had a very strong transcriptional response (640 upregulations and 677 downregulations, P < 0.05). In addition, the magnitude of expression alterations was much higher in K-line than N-line mice. The most significant changes in gene expression were involved in cardiac hypertrophy, cardiac necrosis/cell death, and cardiac infarction. Secreted phosphoprotein 1 and its signaling pathways were upregulated while peroxisome proliferator-activated receptor γ signaling was downregulated in K-line mice. Our study shows that expression of activated NHE1 elicits specific pathways of gene activation in the myocardium that lead to cardiac hypertrophy, cell death, and infarction.

Abstract 265: CITED4 Induces Physiologic Hypertrophy and Improves Cardiac Remodeling After Ischemic Injury

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Vassilios J Bezzerides ◽  
Colin Platt ◽  
Kaavya Paruchuri ◽  
Loren Oh ◽  
Chunyang Xiao ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Cardiac Remodeling ◽  
Systolic Function ◽  
Ischemia Reperfusion ◽  
Ischemic Injury ◽  
Gene Profiling ◽  
Neonatal Rat ◽  
Heart Weight ◽  
Autophagic Flux

Cardiac hypertrophy is an adaptive response to increased hemodynamic stresses, which can be either physiologic, as with exercise, or pathologic, as with valvular heart disease. Recent data suggest that physiologic hypertrophy secondary to exercise may be mediated by the transcription factor CEBPβ and the p300-interacting protein CITED4. We sought to investigate the cardiovascular effects of CITED4 expression in vivo. Using a cardiac-specific and inducible transgenic mouse (Tg) model, we determined the effects of CITED4 expression on cardiac parameters including heart weight, cell size, cardiac function and gene expression. Expression of CITED4 for 3 weeks induced increases in heart weight (22% in HW/TL, p < 0.01) and cardiomyocyte (CM) size (24.5% in cell area, p < 0.001) with normal systolic function and without evidence of fibrosis. Gene profiling demonstrated increased expression of cardiac troponin, a favorable αMHC/βMHC ratio and a reduction in BNP consistent with physiologic hypertrophy. Genome-wide expression profiling of neonatal rat ventricular myocytes (NRVMs) over-expressing CITED4 demonstrated the activation of a unique set of genes including BCL2, ATP12a, Efemp1, Ifi204 and Tcf19. To further examine the potential beneficial role of CITED4, we induced ischemia by transient occlusion of the left anterior descending (LAD) coronary (30 min) followed by reperfusion for 24 hours, 6 days or 4 weeks. At 24 hrs after ischemia-reperfusion injury (IRI), neither cardiac dysfunction on echo nor infarct sizes were different between CITED4 Tg and controls. However, CITED4 Tgs showed substantial recovery of cardiac function at 4 weeks (FS: CITED4 Tg 51%, Control 34%, p < 0.01) and a 3.4-fold reduction in fibrosis (p < 0.005). Analysis of possible cellular responses responsible for the functional recovery demonstrated enhanced autophagic flux with reduced accumulation of LC3II (down 71%, p<0.05) and p62 (down 54%, p<0.005). Further examination of the involved signaling pathway revealed direct activation of mTORC1 and its effectors consistent with a growth phenotype. We conclude that CITED4 expression is sufficient to induce physiologic cardiac hypertrophy and improves cardiac remodeling after ischemic injury likely through activation of mTORC1.

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