scholarly journals The bHLH transcription factor CHF1/Hey2 regulates susceptibility to apoptosis and heart failure after pressure overload

2010 ◽  
Vol 298 (6) ◽  
pp. H2082-H2092 ◽  
Author(s):  
Yonggang Liu ◽  
Man Yu ◽  
Ling Wu ◽  
Michael T. Chin
Keyword(s):  
Heart Failure ◽  
Transcription Factor ◽  
Cardiac Hypertrophy ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Heart Tissue ◽  
Tunel Staining ◽  
Bhlh Transcription Factor ◽  
Gravimetric Analysis ◽  
Aortic Banding

Cardiac hypertrophy is a common response to hemodynamic stress in the heart and can progress to heart failure. To investigate whether the transcription factor cardiovascular basic helix-loop-helix factor 1/hairy/enhancer of split related with YRPW motif 2 (CHF1/Hey2) influences the development of cardiac hypertrophy and progression to heart failure under conditions of pressure overload, we performed aortic constriction on 12-wk-old male wild-type (WT) and heterozygous (HET) mice globally underexpressing CHF1/Hey2. After aortic banding, WT and HET mice showed increased cardiac hypertrophy as measured by gravimetric analysis, as expected. CHF1/Hey2 HET mice, however, demonstrated a greater increase in the ventricular weight-to-body weight ratio compared with WT mice ( P < 0.05). Echocardiographic measurements showed a significantly decreased ejection fraction compared with WT mice ( P < 0.05). Histological examination of Masson trichrome-stained heart tissue demonstrated extensive fibrosis in HET mice compared with WT mice. TUNEL staining demonstrated increased apoptosis in HET hearts ( P < 0.05). Exposure of cultured neonatal myocytes from WT and HET mice to H2O2 and tunicamycin, known inducers of apoptosis that work through different mechanisms, demonstrated significantly increased apoptosis in HET cells compared with WT cells ( P < 0.05). Expression of Bid, a downstream activator of the mitochondrial death pathway, was expressed in HET hearts at increased levels after aortic banding. Expression of GATA4, a transcriptional activator of cardiac hypertrophy, was also increased in HET hearts, as was phosphorylation of GATA4 at Ser105. Our findings demonstrate that CHF1/Hey2 expression levels influence hypertrophy and the progression to heart failure in response to pressure overload through modulation of apoptosis and GATA4 activity.

Abstract 16205: MKP-5 Deficiency Attenuates Pressure Overload-induced Cardiac Hypertrophy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Kisuk Min ◽  
Yan Huang ◽  
Frank J Giordano ◽  
Sudip Bajpeyi ◽  
Anton M Bennett
Keyword(s):  
Heart Failure ◽  
Body Weight ◽  
Cardiac Hypertrophy ◽  
Cardiac Muscle ◽  
Molecular Mechanisms ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Body Weight Ratio ◽  
Pathological Cardiac Hypertrophy

Introduction: Cardiac remodeling occurs in response to pathological stimuli including chronic pressure overload, subsequently leading to heart failure. Despite considerable research efforts, the molecular mechanisms responsible for heart failure have yet to be fully elucidated. One of the prominent signaling pathways involved in the development of pathological cardiac hypertrophy is the mitogen-activated protein kinases (MAPKs) pathways. The MAPKs are inactivated by the MAPK phosphatases (MKPs) through direct dephosphorylation. Growing evidence suggests the importance of MKP-5 signaling mechanisms in physiological and pathological processes. However, the role of MKP-5 has not been explored in cardiac muscle. The objective of this study is to investigate how MKP-5-mediated MAPK activity contributes to mechanisms responsible for pressure overload-induced cardiac hypertrophy. Hypothesis: We tested the hypothesis that MKP-5 serves as a central regulator of MAPKs in pressure overload-induced cardiac hypertrophy. Methods: To investigate the role of MKP-5 in cardiac muscle, we caused pressure overload-induced cardiac hypertrophy in wild type (mkp-5 +/+ ) mice and MKP-5 deficient mice (mkp-5 -/- ) through transverse aortic constriction (TAC). Cardiac function was evaluated by echocardiographic analysis at 4 weeks after TAC. Cardiac hypertrophy was measured by heart-to-body weight ratio. Interstitial myocardial fibrosis was evaluated by Sirius red stains and expression of fibrogenic genes was determined by quantitative PCR. Results: Echocardiographic analysis showed that the ejection fraction and fractional shortening of mkp-5 +/+ mice significantly decreased by at 4 weeks after TAC. Heart-to-body weight ratio increased in mkp-5 +/+ mice. However, MKP-5-deficient heart was protected from cardiac dysfunction and cardiac hypertrophy induced by TAC. Importantly, the fibrogenic genes were markedly reduced in mkp-5 -/- mice as compared with mkp-5 +/+ mice at 4 weeks after TAC. Conclusions: Collectively, our study demonstrates that MKP-5 deficiency prevents the heart from pressure overload-induced cardiac hypertrophy and suggests that MKP-5 may serve as a novel therapeutic target for treatment of heart disease.

Abstract 206: A New MicroRNA Family Regulating Cardiac Autophagy and Hypertrophy

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Thomas Thum ◽  
Shashi K Gupta ◽  
Ahmet Ucar ◽  
Jan Fiedler ◽  
Leon DeWindt ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transcription Factor ◽  
Cardiac Hypertrophy ◽  
Cardiac Failure ◽  
Pressure Overload ◽  
Hypertrophic Growth ◽  
Pathological Cardiac Hypertrophy ◽  
Microrna Family ◽  
Causes Of Mortality ◽  
Necessary And Sufficient

Pathologic growth of cardiomyocytes and derailed autophagy are major determinants for the development of heart failure, one of the leading medical causes of mortality worldwide. Here, we show the microRNA (miRNA)-212/132 family to regulate hypertrophy and autophagy in cardiomyocytes. Hypertrophic stimuli lead to the upregulation of miR-212 and miR-132 expression in cardiomyocytes, which are both necessary and sufficient to drive the hypertrophic growth of cardiomyocytes. MiR-212/132 null mice are protected from pressure-overload induced heart failure, whereas cardiomyocyte-specific overexpression of the miR-212/132 family leads to pathological cardiac hypertrophy, heart failure and lethality in mice. Mechanistically, both miR-212 and miR-132 directly target the anti-hypertrophic and pro-autophagic FoxO3 transcription factor and overexpression of these miRNAs leads to hyperactivation of pro-hypertrophic calcineurin/NFAT signalling and impaired autophagic response upon starvation. Pharmacologic miRNA inhibition by antagomir injection rescues cardiac hypertrophy and heart failure in mice, offering a possible therapeutic approach for cardiac failure.

Abstract 208: Parkin Contributes to the Development of Cardiac Hypertrophy in Response to Cardiac Pressure Overload

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Sarah E Shires ◽  
Dieter A Kubli ◽  
Eileen R Gonzalez ◽  
Nicole H Purcell ◽  
Åsa B Gustafsson
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Expression Profiles ◽  
Rapid Development ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Heart Weight ◽  
Loss Of Function ◽  
Functional Importance ◽  
Knock Out

Parkin is an E3 ubiquitin ligase known to mediate mitochondrial clearance by marking damaged mitochondria for autophagy. Our lab has previously shown that Parkin is important for stress adaptation following myocardial infarction, and that loss of Parkin leads to accumulation of dysfunctional mitochondria. However, whether Parkin plays a role in cardiac adaptation to pressure overload is currently unknown. Here we investigated the functional importance of Parkin in cardiac hypertrophy and development of heart failure in response to hemodynamic stress. Wild type (WT), Parkin knock out (Parkin -/- ), and cardiac-specific Parkin transgenic (Parkin-TG) mice were subjected to trans-aortic constriction (TAC). Cardiac anatomy and function was evaluated by histology and echocardiography. Inflammation and hypertrophy gene expression profiles were assessed using qPCR and immunohistochemistry. We discovered that after 2 weeks of TAC, cardiac hypertrophy markers were not increased in hearts from Parkin -/- mice, and there was no increase in the heart weight to body weight ratio (HW/BW). However, after 8 weeks of TAC, Parkin -/- mice showed similar cardiac hypertrophy and loss of function as WT hearts. Parkin deficient hearts also displayed increased interstitial and perivascular fibrosis compared to WT hearts after 8 weeks of TAC. This suggests that there is a delay in activating the hypertrophy program in the absence of Parkin, and that lack of Parkin leads to excessive fibrosis. In contrast, Parkin-TG mice showed a rapid development of hypertrophy and progression to heart failure compared to WT mice. Interestingly, we observed no differences in either mitochondrial content or LC3 levels after two weeks of TAC in Parkin-TG hearts, suggesting that the rapid development of hypertrophy and early progression to heart failure was not due to excessive mitophagy. These data suggest that Parkin plays an important role in the activation of the cardiac hypertrophy program and that this function may be independent of its role in regulating mitophagy. Thus, this study provides novel insight into the functional importance of Parkin in the heart. Additional studies are needed to determine the mechanism of how Parkin regulates cardiac hypertrophy.

Sarcolemmal Ca2+ transport activities in cardiac hypertrophy caused by pressure overload

1989 ◽  
Vol 257 (2) ◽  
pp. H349-H356 ◽  
Author(s):  
H. Nakanishi ◽  
N. Makino ◽  
T. Hata ◽  
H. Matsui ◽  
K. Yano ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Atpase Activity ◽  
Initial Rate ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Hypertensive Rats ◽  
Body Weight Ratio ◽  
Aortic Banding ◽  
Spontaneously Hypertensive ◽  
Ca2 Channels

To examine Ca2+ transport activities in sarcolemmal membrane in cardiac hypertrophy caused by pressure overload, rats were subjected to aortic banding for 28 days. Heart-to-body weight ratio was increased by 46% in aortic-banded animals in comparison with the sham-operated rats. Ouabain-sensitive Na+-K+-ATPase activity in sarcolemma (SL) from hypertrophied hearts was not different from that in the control preparation. The initial rate of Na+-dependent Ca2+ uptake in SL vesicles from the hypertrophied hearts was stimulated by 53% compared with the control vesicles. ATP-dependent Ca2+ uptake and Ca2+-stimulated adenosinetriphosphatase (ATPase) activities in SL from hypertrophied hearts were increased by 35%. The number of Ca2+ channels estimated by [5-methyl-3H]nitrendipine binding was decreased by 33% in SL from hypertrophied hearts. Total and individual phospholipid contents in the hypertrophied heart preparations were not different from those in the control, except that phosphatidylcholine and phosphatidylethanolamine contents were significantly increased. Sarcolemmal preparations from hypertrophied hearts from the 22-wk-old spontaneously hypertensive rats exhibited changes in Na+-Ca2+ exchange and Ca2+-pump activities (similar to those observed in banded hearts), whereas the Na+-K+-ATPase activity decreased, [3H]nitrendipine binding increased, and phospholipid contents were not different. Thus, although differences were defined between two types of hypertrophy, these results suggest alterations in the sarcolemmal Ca2+ transport activities that may serve as an adaptive mechanism for the removal of Ca2+ from the myocardial cells during the development of cardiac hypertrophy.

scholarly journals Oxidative Stress as A Mechanism for Functional Alterations in Cardiac Hypertrophy and Heart Failure

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 931
Author(s):  
Anureet K. Shah ◽  
Sukhwinder K. Bhullar ◽  
Vijayan Elimban ◽  
Naranjan S. Dhalla
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Cardiac Dysfunction ◽  
Critical Role ◽  
Pressure Overload ◽  
Hypertrophied Heart ◽  
Vasoactive Hormones

Although heart failure due to a wide variety of pathological stimuli including myocardial infarction, pressure overload and volume overload is associated with cardiac hypertrophy, the exact reasons for the transition of cardiac hypertrophy to heart failure are not well defined. Since circulating levels of several vasoactive hormones including catecholamines, angiotensin II, and endothelins are elevated under pathological conditions, it has been suggested that these vasoactive hormones may be involved in the development of both cardiac hypertrophy and heart failure. At initial stages of pathological stimuli, these hormones induce an increase in ventricular wall tension by acting through their respective receptor-mediated signal transduction systems and result in the development of cardiac hypertrophy. Some oxyradicals formed at initial stages are also involved in the redox-dependent activation of the hypertrophic process but these are rapidly removed by increased content of antioxidants in hypertrophied heart. In fact, cardiac hypertrophy is considered to be an adaptive process as it exhibits either normal or augmented cardiac function for maintaining cardiovascular homeostasis. However, exposure of a hypertrophied heart to elevated levels of circulating hormones due to pathological stimuli over a prolonged period results in cardiac dysfunction and development of heart failure involving a complex set of mechanisms. It has been demonstrated that different cardiovascular abnormalities such as functional hypoxia, metabolic derangements, uncoupling of mitochondrial electron transport, and inflammation produce oxidative stress in the hypertrophied failing hearts. In addition, oxidation of catecholamines by monoamine oxidase as well as NADPH oxidase activation by angiotensin II and endothelin promote the generation of oxidative stress during the prolonged period by these pathological stimuli. It is noteworthy that oxidative stress is known to activate metallomatrix proteases and degrade the extracellular matrix proteins for the induction of cardiac remodeling and heart dysfunction. Furthermore, oxidative stress has been shown to induce subcellular remodeling and Ca2+-handling abnormalities as well as loss of cardiomyocytes due to the development of apoptosis, necrosis, and fibrosis. These observations support the view that a low amount of oxyradical formation for a brief period may activate redox-sensitive mechanisms, which are associated with the development of cardiac hypertrophy. On the other hand, high levels of oxyradicals over a prolonged period may induce oxidative stress and cause Ca2+-handling defects as well as protease activation and thus play a critical role in the development of adverse cardiac remodeling and cardiac dysfunction as well as progression of heart failure.

Abstract 3773: Myotrophin and the p53 Signaling Cascade in Cardiac Hypertrophy/Heart Failure

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Biswajit Das ◽  
David Young ◽  
Amit Vasanji ◽  
Sudhiranjan Gupta ◽  
Zoran Popovic ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Expression Profiles ◽  
Gene Array ◽  
Weight Ratio ◽  
Signaling Cascade ◽  
Mobility Shift ◽  
Transgenic Mouse Line ◽  
P53 Signaling

Myotrophin (Myo), a 12-kDa protein, stimulates myocyte growth and is a factor in initiating cardiac hypertrophy (CH). Cardiospecific overexpression of Myo in transgenic mice (Myo-Tg) induces hypertrophy that progresses to heart failure (HF). Oligonucleotide gene array revealed upregulation of a p53 homologue gene (EST- AI843106 ) in Myo-Tg mice during HF, indicating that p53 plays an important role during the transition of hypertrophy to HF. To dissect out the mechanisms of p53-mediated Myo-induced CH/HF, we developed a double-transgenic mouse line (p53 −/− /myo +/+ ) by crossing Myo-Tg mice with p53-null mice. The double transgenic mice showed a significant attenuation of cardiac mass compared to Myo-Tg mice (heart weight:body weight ratio; 5.2 ± 0.21 vs. 7.9 ± 0.58, p < 0.001) associated with improved cardiac function and downregulation of ANF expression, suggesting that hypertrophy induced by Myo overexpression is indeed mediated through p53. To elucidate the relationship between p53 and Myo-induced hypertrophy, we performed a Reverse-Transcription Real-Time PCR pathway array on heart tissues from p53 −/− /myo +/+ vs. Myo-Tg mice. A bioinformatic approach, Ingenuity Pathway Analysis TM (IPA), was used to analyze the selected up-/downregulated genes. The IPA network showed that among the up-/downregulated genes, Bcl2, Brca1, Cdkn1a and Myc occupy the nodal position, whereas E2f1 , Pmaip1 , Gadd45a and Pttg1 function as peripheral candidates. The expression profiles of some genes of the p53 pathway were validated by immunoblot analysis. Functional assignment of these selected candidate genes showed that Bcl2, E2f1 and FasL are related to CH/HF, but the function of Gadd45a, Pmaip1, and Vcan is still unknown. Apart from these p53 cascade members, we also found that other molecules (e.g., Jnk, Ras, NF-kB, Cyclin L, and Mek) may be involved in an intricate interplay to stimulate p53-mediated Myo-induced CH. Suppression of NF-kB activity (by electrophoresis mobility shift assay) in p53 −/− /myo +/+ mice compared to Myo-Tg mice indicated involvement of NF-kB, as predicted by IPA, in Myo/p53 cross-talk. Our data suggest that the p53 signaling cascade actively participates in progression of hypertrophy to HF, triggered by overexpression of myotrophin.

Abstract 350: Atorvastatin Attenuates Pressure Overload-induced Cardiac Hypertrophy and Dysfunction Through Enhanced Autophagy

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Zhuo Zhao ◽  
Wei Wang ◽  
Hua-Ting Wang ◽  
Qing-Xin Geng ◽  
Di Zhao ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Western Blot ◽  
Mrna Level ◽  
Mammalian Target Of Rapamycin ◽  
Pressure Overload ◽  
Oral Gavage ◽  
Atorvastatin Treatment ◽  
Developing Heart ◽  
Phosphorylated Akt

Aims: Cardiac hypertrophy is a maladaptive change in response to pressure overload and is also an important risk for developing heart failure. We previously demonstrated that atorvastatin inhibits cardiac hypertrophy and remodeling in a mouse model of transverse aorta constriction (TAC). This study was designed to determine the regulation of atorvastatin on cardiac autophagy and its association with the development of cardiac hypertrophy and dysfunction in the mice TAC model. Methods and results: TAC or sham operations were performed in male C57/L6 mice at 8 weeks of age. Atorvastatin (50 mg/kg/day) or vehicle (normal saline) were administered daily by oral gavage to TAC mice (n=10 per group). Echocardiography and real-time PCR data showed that chronic atorvastatin treatment for four weeks significantly attenuated pressure overload-induced cardiac hypertrophy and dysfunction, as well as cardiac mRNA level of atrial natriuretic factor (ANF), a biomarker of cardiac hypertrophy and heart failure. After 4 weeks of TAC, results from electron microscopy and Western blot showed that cardiac autophagy was activated, evidenced by the increased expression of microtubule-associated protein-1 light chain 3-II (LC3-II), Beclin-1, caspase-3, and the formation of autophagosomes. Interestingly, cardiac autophagy was further increased by the treatment of atorvastatin for 4 weeks. Western blot analysis showed phosphorylated Akt and mammalian target of rapamycin (p-mTor) decreased in the heart of TAC versus sham mice, which were further decreased by atorvastatin treatment. Conclusions: These findings suggest that atorvastatin attenuates cardiac hypertrophy and dysfunction in TAC mice probably through its regulation on cardiac autophagy via Akt/mTor pathways.

Collagen characterization in volume-overload- and pressure-overload-induced cardiac hypertrophy in minipigs

1993 ◽  
Vol 265 (2) ◽  
pp. H434-H438 ◽  
Author(s):  
J. Harper ◽  
E. Harper ◽  
J. W. Covell
Keyword(s):  
Cardiac Hypertrophy ◽  
Porcine Model ◽  
Pressure Overload ◽  
Volume Overload ◽  
Heart Tissue ◽  
Canine Heart ◽  
Cross Link ◽  
Collagen Types ◽  
Collagen Concentration ◽  
Pepsin Digestion

Previous studies in several different species have shown reduced extractability of collagens in some types of cardiac hypertrophy (volume overload) but not others (pressure overload). The objective of the present study was to examine collagen proteins from the same species (minipigs) with both pressure-overload- and volume-overload-induced cardiac hypertrophy. Hypertrophy was induced by two methods: thoracic banding of the aorta to create pressure overload and arteriovenous shunt to cause volume overload in a porcine model. Collagen types I, III, IV, and V were isolated by pepsin digestion from normal and hypertrophied pig left ventricle tissues. Types I and III collagens from normal and hypertrophied samples, when separated from types IV and V, were digested with cyanogen bromide (CB), and the peptides were examined. Collagen concentration was increased in myocardium removed from hearts subjected to volume overload and unchanged in hearts subjected to pressure overload. The extractability of total collagen was unaffected in pressure-overloaded left ventricles but lower in samples from volume-overloaded hearts. CB digestion cleaved all of the types I and III collagens into similar smaller CB peptides with the exception of a 100-kDa peptide that was observed in both control and hypertrophied hearts. This peptide corresponds to one of the high-molecular-weight peptides found in canine heart tissue. The mature collagen cross-link hydroxylysylpyridinoline (HP) was identified in normal and hypertrophied types I and III collagen from porcine sources. Pressure-overload- and volume-overload-induced cardiac hypertrophy in the pig produced different alterations in the extracellular matrix.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Bakuchiol protects against pathological cardiac hypertrophy by blocking NF-κB signaling pathway

2018 ◽  
Vol 38 (5) ◽  
Author(s):  
Zheng Wang ◽  
Lu Gao ◽  
Lili Xiao ◽  
Lingyao Kong ◽  
Huiting Shi ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Signaling Pathway ◽  
Pressure Overload ◽  
Neonatal Rat ◽  
Oral Gavage ◽  
Aortic Banding ◽  
Rat Cardiomyocytes ◽  
Pathological Cardiac Hypertrophy ◽  
First Time

Bakuchiol (Bak), a monoterpene phenol isolated from the seeds of Psoralea corylifolia, has been widely used to treat a large variety of diseases in both Indian and Chinese folkloric medicine. However, the effects of Bak on cardiac hypertrophy remain unclear. Therefore, the present study was designed to determine whether Bak could alleviate cardiac hypertrophy. Mice were subjected to aortic banding (AB) to induce cardiac hypertrophy model. Bak of 1 ml/100 g body weight was given by oral gavage once a day from 1 to 8 weeks after surgery. Our data demonstrated for the first time that Bak could attenuate pressure overload-induced cardiac hypertrophy and could attenuate fibrosis and the inflammatory response induced by AB. The results further revealed that the effect of Bak on cardiac hypertrophy was mediated by blocking the activation of the NF-κB signaling pathway. In vitro studies performed in neonatal rat cardiomyocytes further proved that the protective effect of Bak on cardiac hypertrophy is largely dependent on the NF-κB pathway. Based on our results, Bak shows profound potential for its application in the treatment of pathological cardiac hypertrophy, and we believe that Bak may be a promising therapeutic candidate to treat cardiac hypertrophy and heart failure.

A gene therapeutic approach to inhibit calcium and integrin binding protein 1 ameliorates maladaptive remodelling in pressure overload

2018 ◽  
Vol 115 (1) ◽  
pp. 71-82 ◽  
Author(s):  
Andrea Grund ◽  
Malgorzata Szaroszyk ◽  
Janina K Döppner ◽  
Mona Malek Mohammadi ◽  
Badder Kattih ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Binding Protein ◽  
Treatment Strategies ◽  
Pressure Overload ◽  
Cellular Growth ◽  
Neonatal Rat ◽  
Rat Cardiomyocytes ◽  
Pathological Cardiac Hypertrophy

Abstract Aims Chronic heart failure is becoming increasingly prevalent and is still associated with a high mortality rate. Myocardial hypertrophy and fibrosis drive cardiac remodelling and heart failure, but they are not sufficiently inhibited by current treatment strategies. Furthermore, despite increasing knowledge on cardiomyocyte intracellular signalling proteins inducing pathological hypertrophy, therapeutic approaches to target these molecules are currently unavailable. In this study, we aimed to establish and test a therapeutic tool to counteract the 22 kDa calcium and integrin binding protein (CIB) 1, which we have previously identified as nodal regulator of pathological cardiac hypertrophy and as activator of the maladaptive calcineurin/NFAT axis. Methods and results Among three different sequences, we selected a shRNA construct (shCIB1) to specifically down-regulate CIB1 by 50% upon adenoviral overexpression in neonatal rat cardiomyocytes (NRCM), and upon overexpression by an adeno-associated-virus (AAV) 9 vector in mouse hearts. Overexpression of shCIB1 in NRCM markedly reduced cellular growth, improved contractility of bioartificial cardiac tissue and reduced calcineurin/NFAT activation in response to hypertrophic stimulation. In mice, administration of AAV-shCIB1 strongly ameliorated eccentric cardiac hypertrophy and cardiac dysfunction during 2 weeks of pressure overload by transverse aortic constriction (TAC). Ultrastructural and molecular analyses revealed markedly reduced myocardial fibrosis, inhibition of hypertrophy associated gene expression and calcineurin/NFAT as well as ERK MAP kinase activation after TAC in AAV-shCIB1 vs. AAV-shControl treated mice. During long-term exposure to pressure overload for 10 weeks, AAV-shCIB1 treatment maintained its anti-hypertrophic and anti-fibrotic effects, but cardiac function was no longer improved vs. AAV-shControl treatment, most likely resulting from a reduction in myocardial angiogenesis upon downregulation of CIB1. Conclusions Inhibition of CIB1 by a shRNA-mediated gene therapy potently inhibits pathological cardiac hypertrophy and fibrosis during pressure overload. While cardiac function is initially improved by shCIB1, this cannot be kept up during persisting overload.

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