scholarly journals Microfibrillar-Associated Protein 4 Regulates Stress-Induced Cardiac Remodeling

2021 ◽  
Author(s):  
Lisa E Dorn ◽  
William R Lawrence ◽  
Jennifer Petrosino ◽  
Xianyao Xu ◽  
Thomas J Hund ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Matrix Protein ◽  
Treatment Options ◽  
Pressure Overload ◽  
Extracellular Matrix Protein ◽  
Cardiomyocyte Hypertrophy ◽  
Hypertrophic Growth

Rationale: Cardiac hypertrophy, a major risk factor for heart failure, occurs when cardiomyocytes remodel in response to complex signaling induced by injury or cell stress. Although cardiomyocytes are the ultimate effectors of cardiac hypertrophy, non-myocyte populations play a large yet understudied role in determining how cardiomyocytes respond to stress. Objective: To identify novel paracrine regulators of cardiomyocyte hypertrophic remodeling. Methods and Results: : We have identified a novel role for a non-myocyte-derived and TGFbeta1-induced extracellular matrix protein Microfibrillar-associated protein 4 (MFAP4) in the pathophysiology of cardiac remodeling. We have determined that non-myocyte cells are the primary sources of MFAP4 in the heart in response to TGFbeta1 stimulation. Furthermore, we have demonstrated a crucial role of MFAP4 in the cardiac adaptation to stress. Global knockout of MFAP4 led to increased cardiac hypertrophy and worsened cardiac function following chronic pressure overload. Also, one week of angiotensin-mediated neurohumoral stimulation was sufficient to exacerbate cardiomyocyte hypertrophy in MFAP4 null mice. In contrast, administration of exogenous MFAP4 to isolated cardiomyocytes blunted their phenylephrine-induced hypertrophic growth through an integrin-dependent mechanism. Finally, MFAP4 deficiency leads to dysregulated integration of G protein-coupled receptor and integrin signaling in the heart. Conclusions: Altogether, our results demonstrate a critical paracrine role of MFAP4 in the development of cardiac hypertrophy and could inform future treatment options for heart failure patients.

scholarly journals Autophagy modulation: a potential therapeutic approach in cardiac hypertrophy

2017 ◽  
Vol 313 (2) ◽  
pp. H304-H319 ◽  
Author(s):  
Xuejun Wang ◽  
Taixing Cui
Keyword(s):  
Heart Failure ◽  
Quality Control ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Pressure Overload ◽  
Energy Crisis ◽  
Pathogenic Role ◽  
Evolutionarily Conserved ◽  
Control Survival

Autophagy is an evolutionarily conserved process used by the cell to degrade cytoplasmic contents for quality control, survival for temporal energy crisis, and catabolism and recycling. Rapidly increasing evidence has revealed an important pathogenic role of altered activity of the autophagosome-lysosome pathway (ALP) in cardiac hypertrophy and heart failure. Although an early study suggested that cardiac autophagy is increased and that this increase is maladaptive to the heart subject to pressure overload, more recent reports have overwhelmingly supported that myocardial ALP insufficiency results from chronic pressure overload and contributes to maladaptive cardiac remodeling and heart failure. This review examines multiple lines of preclinical evidence derived from recent studies regarding the role of autophagic dysfunction in pressure-overloaded hearts, attempts to reconcile the discrepancies, and proposes that resuming or improving ALP flux through coordinated enhancement of both the formation and the removal of autophagosomes would benefit the treatment of cardiac hypertrophy and heart failure resulting from chronic pressure overload.

P2590A liver-derived secretory protein, selenoprotein P causes pressure overload-induced cardiac hypertrophys

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
S Usui ◽  
S Takashima ◽  
O Inoue ◽  
C Goten ◽  
Y Takeda ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Pressure Overload ◽  
Selenoprotein P ◽  
Lung Weight ◽  
Hepatic Expression

Abstract Background Hepatokine selenoprotein P (SeP) contributes to insulin resistance and hyperglycemia in patients with type 2 diabetes. Inhibition of SeP protects the heart from ischemia reperfusion injury and serum levels of SeP are elevated in patients with heart failure with reduced ejection fraction. Objective We investigated the role of SeP in the regulation of cardiac remodeling in response to pressure overload. Methods and results To examine the role of SeP in cardiac remodeling, transverse aortic constriction (TAC) was subjected to SeP knockout (KO) and wild-type (WT) mice for 2 weeks. Hepatic expression of SeP in WT was significantly increased by TAC. LV weight/tibial length (TL) was significantly smaller in SeP KO mice than in WT mice (6.75±0.24 vs 8.33±0.32, p<0.01). Lung weight/TL was significantly smaller in SeP KO than in WT mice (10.46±0.44 vs 16.38±1.12, p<0.05). TAC-induced cardiac upregulation of the fetal type genes, including atrial and brain natriuretic factors, was significantly attenuated in SeP KO compared to WT. Furthermore, azan staining revealed that there was significantly less interstitial fibrosis in hearts after TAC in SeP KO than in WT mice. To determine whether hepatic overexpression of SeP affects TAC-induced cardiac hypertrophy, a hydrodynamic injection method was used to generate mice that overexpress SeP mRNA in the liver. Hepatic overexpression of SeP in SeP KO mice lead to a significant increase in LV weight/TL and Lung weight/TL after TAC compared to that in other SeP KO mice. Conclusions These results suggest that cardiac pressure overload induced hepatic expression of SeP and the absence of endogenous SeP attenuated cardiac hypertrophy, dysfunction and fibrosis in response to pressure overload in mice. SeP possibly plays a maladaptive role against progression of heart failure through the liver-heart axis.

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.

scholarly journals Piezo1-Mediated Mechanotransduction Promotes Cardiac Hypertrophy by Impairing Calcium Homeostasis to Activate Calpain/Calcineurin Signaling

Hypertension ◽  
2021 ◽  
Author(s):  
Yuhao Zhang ◽  
Sheng-an Su ◽  
Wudi Li ◽  
Yuankun Ma ◽  
Jian Shen ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Ion Channel ◽  
Calcium Homeostasis ◽  
Pressure Overload ◽  
Cell Physiology ◽  
Hypertrophic Growth ◽  
Molecular Features ◽  
Mechanosensitive Ion Channel

Hemodynamic overload induces pathological cardiac hypertrophy, which is an independent risk factor for intractable heart failure in long run. Beyond neurohumoral regulation, mechanotransduction has been recently recognized as a major regulator of cardiac hypertrophy under a myriad of conditions. However, the identification and molecular features of mechanotransducer on cardiomyocytes are largely sparse. For the first time, we identified Piezo1 (Piezo type mechanosensitive ion channel component 1), a novel mechanosensitive ion channel with preference to Ca 2+ was remarkably upregulated under pressure overload and enriched near T-tubule and intercalated disc of cardiomyocyte. By applying cardiac conditional Piezo1 knockout mice (Piezo1 fl/fl Myh6Cre+, Piezo1 Cko ) undergoing transverse aortic constriction, we demonstrated that Piezo1 was required for the development of cardiac hypertrophy and subsequent adverse remodeling. Activation of Piezo1 by external mechanical stretch or agonist Yoda1 lead to the enlargement of cardiomyocytes in vitro, which was blocked by Piezo1 silencing or Yoda1 analog Dooku1 or Piezo1 inhibitor GsMTx4. Mechanistically, Piezo1 perturbed calcium homeostasis, mediating extracellular Ca 2+ influx and intracellular Ca 2+ overload, thereby increased the activation of Ca 2+ -dependent signaling, calcineurin, and calpain. Inhibition of calcineurin or calpain could abolished Yoda1 induced upregulation of hypertrophy markers and the hypertrophic growth of cardiomyocytes in vitro. From a comprehensive view of the cardiac transcriptome, most of Piezo1 affected genes were highly enriched in muscle cell physiology, tight junction, and corresponding signaling. This study characterizes an undefined role of Piezo1 in pressure overload induced cardiac hypertrophy. It may partially decipher the differential role of calcium under pathophysiological condition, implying a promising therapeutic target for cardiac dysfunction.

Abstract 354: The Role of the Liver Heart Axis During Cardiac Remodeling

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Soichiro Usui ◽  
Shin-ichiro Takashima ◽  
Kenji Sakata ◽  
Masa-aki Kawashiri ◽  
Masayuki Takamura
Keyword(s):  
Heart Failure ◽  
Insulin Resistance ◽  
Cardiac Remodeling ◽  
Pressure Overload ◽  
Normal Subjects ◽  
Serum Levels ◽  
Lung Weight ◽  
Reduced Ejection Fraction ◽  
Hepatic Expression

Background: Hepatokine selenoprotein P (SeP) contributes to insulin resistance and hyperglycemia in patients with type 2 diabetes. Although clinical studies suggest the insulin resistance is an independent risk factor of heart failure and inhibition of SeP protects the heart from ischemia reperfusion injury, the role of SeP in pathogenesis of chronic heart failure is not well understood. Objective: We examined the role of SeP in the regulation of cardiac remodeling in response to pressure overload. Methods and Results: We measured serum SeP levels in 22 patients for heart failure with reduced ejection fraction (HFrEF; LVEF<50%) and 22 normal subjects. Serum levels of SeP were significantly elevated in patients with HFrEF compared to in normal subjects (3.55 ± 0.43 vs 2.98 ± 0.43, p<0.01). To examine the role of SeP in cardiac remodeling, SeP knockout (KO) and wild-type (WT) mice were subjected to pressure overload (transverse aortic constriction (TAC)) for 2 weeks. The mortality rate following TAC was significantly decreased in SeP KO mice compared to WT mice (22.5 % in KO mice (n=40) vs 52.3 % in WT mice (n=39) p<0.01). LV weight/tibial length (TL) was significantly smaller in SeP KO mice than in WT mice (6.75 ± 0.24 vs 8.33 ± 0.32, p<0.01). Lung weight/TL was significantly smaller in SeP KO than in WT mice (10.46 ± 0.44 vs 16.38 ± 1.12, p<0.05). Interestingly, hepatic expression of SeP in WT was significantly increased by TAC. To determine whether hepatic overexpression of SeP affects TAC-induced cardiac hypertrophy, a hydrodynamic injection method was used to generate mice that overexpress SeP mRNA in the liver. Hepatic overexpression of SeP in SeP KO mice lead to a significant increase in LV weight/TL and Lung weight/TL after TAC compared to that in other SeP KO mice. Conclusions: These results suggest that serum levels of SeP were elevated in patients with heart failure with reduced ejection fraction and cardiac pressure overload induced hepatic expression of SeP in mice model. Gene deletion of SeP attenuated cardiac hypertrophy and dysfunction in response to pressure overload in mice. SeP possibly plays a pivotal role in promoting cardiac remodeling through the liver-heart axis.

Cacao Bean Polyphenols Inhibit Cardiac Hypertrophy and Systolic Dysfunction in Pressure Overload-induced Heart Failure Model Mice

Planta Medica ◽  
2020 ◽  
Vol 86 (17) ◽  
pp. 1304-1312
Author(s):  
Nurmila Sari ◽  
Yasufumi Katanasaka ◽  
Hiroki Honda ◽  
Yusuke Miyazaki ◽  
Yoichi Sunagawa ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Gene Transcription ◽  
Binding Protein ◽  
Systolic Dysfunction ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal

AbstractPathological stresses such as pressure overload and myocardial infarction induce cardiac hypertrophy, which increases the risk of heart failure. Cacao bean polyphenols have recently gained considerable attention for their beneficial effects on cardiovascular diseases. This study investigated the effect of cacao bean polyphenols on the development of cardiac hypertrophy and heart failure. Cardiomyocytes from neonatal rats were pre-treated with cacao bean polyphenols and then stimulated with 30 µM phenylephrine. C57BL/6j male mice were subjected to sham or transverse aortic constriction surgery and then orally administered with vehicle or cacao bean polyphenols. Cardiac hypertrophy and function were examined by echocardiography. In cardiomyocytes, cacao bean polyphenols significantly suppressed phenylephrine-induced cardiomyocyte hypertrophy and hypertrophic gene transcription. Extracellular signal-regulated kinase 1/2 and GATA binding protein 4 phosphorylation induced by phenylephrine was inhibited by cacao bean polyphenols treatment in the cardiomyocytes. Cacao bean polyphenols treatment at 1200 mg/kg significantly ameliorated left ventricular posterior wall thickness, fractional shortening, hypertrophic gene transcription, cardiac hypertrophy, cardiac fibrosis, and extracellular signal-regulated kinase 1/2 phosphorylation induced by pressure overload. In conclusion, these findings suggest that cacao bean polyphenols prevent pressure overload-induced cardiac hypertrophy and systolic dysfunction by inhibiting the extracellular signal-regulated kinase 1/2-GATA binding protein 4 pathway in cardiomyocytes. Thus, cacao bean polyphenols may be useful for heart failure therapy in humans.

scholarly journals Role of CyPA in cardiac hypertrophy and remodeling

2019 ◽  
Vol 39 (12) ◽  
Author(s):  
Mengfei Cao ◽  
Wei Yuan ◽  
Meiling Peng ◽  
Ziqi Mao ◽  
Qianru Zhao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Interstitial Fibrosis ◽  
Systolic Function ◽  
Cardiac Fibroblasts ◽  
Cardiomyocyte Hypertrophy ◽  
Pathological Cardiac Hypertrophy ◽  
Complex Process

Abstract Pathological cardiac hypertrophy is a complex process and eventually develops into heart failure, in which the heart responds to various intrinsic or external stress, involving increased interstitial fibrosis, cell death and cardiac dysfunction. Studies have shown that oxidative stress is an important mechanism for this maladaptation. Cyclophilin A (CyPA) is a member of the cyclophilin (CyPs) family. Many cells secrete CyPA to the outside of the cells in response to oxidative stress. CyPA from blood vessels and the heart itself participate in a variety of signaling pathways to regulate the production of reactive oxygen species (ROS) and mediate inflammation, promote cardiomyocyte hypertrophy and proliferation of cardiac fibroblasts, stimulate endothelial injury and vascular smooth muscle hyperplasia, and promote the dissolution of extracellular matrix (ECM) by activating matrix metalloproteinases (MMPs). The events triggered by CyPA cause a decline of diastolic and systolic function and finally lead to the occurrence of heart failure. This article aims to introduce the role and mechanism of CyPA in cardiac hypertrophy and remodeling, and highlights its potential role as a disease biomarker and therapeutic target.

Abstract 1271: IKKβ/NF-κB Pathway Protects Hearts from Hemodynamic Stress Mediated through Regulating MnSOD Expression

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Shungo Hikoso ◽  
Kinya Otsu ◽  
Osamu Yamaguchi ◽  
Toshihiro Takeda ◽  
Masayuki Taniike ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cardiac Remodeling ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Negative Regulator ◽  
Iκb Kinase ◽  
Jnk Activation

Objectives: We have previously reported that NF-κB contributes to GPCR agonist-induced hypertrophy in cultured cardiomyocytes. However, the in vivo role of this pathway in the pathogenesis of cardiac remodeling remains to be elucidated. Although IκB kinase β (IKKβ)/NF-κB pathway is a major negative regulator of cell death, it can sensitize cells to death-inducing stimuli in some instances, thus it can be either anti- or pro-apoptotic. In this study, we aimed to clarify the role of IKKβ/NF-κB signaling in cardiac remodeling using cardiac-specific IKKβ deficient mice. Methods and Results: We crossed mice bearing an IKK β flox allele with mice expressing the Cre recombinase under the control of the myosin light chain 2v promoter ( MLC2v-Cre +/− ) to generate IKK β flox/flox ; MLC2v-Cre +/− mice (conditional knockout:CKO). Then, CKO mice (n=14) and control littermates bearing IKK β flox/flox (CTRL, n=14) were subjected to pressure overload by means of transverse aortic constriction (TAC). EMSA analysis revealed NF-κB DNA binding activity after TAC had attenuated in CKO hearts. One week after TAC, echocardiography showed significantly lower left ventricular fractional shortening (26.9±2.7% vs. 41.4±0.9%, p<0.01), and higher left ventricular end-diastolic dimension (4.02±0.14 mm vs. 3.47±0.08 mm, p<0.01) and lung weight/body weight ratio (11.1±1.4 vs. 5.5±0.1, p<0.01) in CKO mice compared with CTRL mice, indicating the development of heart failure in CKO mice. Number of apoptotic cells had increased in CKO hearts after TAC, suggesting that the enhanced apoptosis is a cause for heart failure. The expression levels of MnSOD mRNA and protein after TAC, which is one of NF-κB target genes, were significantly lower in CKO than those in CTRL mice. As a consequence, oxidative stress and JNK activation in CKO hearts after TAC had significantly increased compared with those in CTRL heart, suggesting that increased oxidative stress and enhanced JNK activity resulted in cardiomyocyte apoptosis in CKO hearts. Conclusion: These results show that IKKβ/NF-κB pathway in cardiomyocyte plays a protective role mediated through attenuation of oxidative stress and JNK activation in response to pressure overload.

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.

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