TMEM173 protects against pressure overload‐induced cardiac hypertrophy by modulating autophagy

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.

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Cardiac Hypertrophy Changes Compartmentation of cAMP in Non-Raft Membrane Microdomains

Cells ◽

10.3390/cells10030535 ◽

2021 ◽

Vol 10 (3) ◽

pp. 535

Author(s):

Nikoleta Pavlaki ◽

Kirstie A. De Jong ◽

Birgit Geertz ◽

Viacheslav O. Nikolaev ◽

Alexander Froese

Keyword(s):

Cardiac Hypertrophy ◽

Ventricular Myocytes ◽

Resonance Energy Transfer ◽

Pressure Overload ◽

Resonance Energy ◽

Cyclic Adenosine Monophosphate ◽

Adenosine Monophosphate ◽

Differential Regulation ◽

Membrane Microdomains ◽

Transgenic Mouse Line

3′,5′-Cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger which plays critical roles in cardiac function and disease. In adult mouse ventricular myocytes (AMVMs), several distinct functionally relevant microdomains with tightly compartmentalized cAMP signaling have been described. At least two types of microdomains reside in AMVM plasma membrane which are associated with caveolin-rich raft and non-raft sarcolemma, each with distinct cAMP dynamics and their differential regulation by receptors and cAMP degrading enzymes phosphodiesterases (PDEs). However, it is still unclear how cardiac disease such as hypertrophy leading to heart failure affects cAMP signals specifically in the non-raft membrane microdomains. To answer this question, we generated a novel transgenic mouse line expressing a highly sensitive Förster resonance energy transfer (FRET)-based biosensor E1-CAAX targeted to non-lipid raft membrane microdomains of AMVMs and subjected these mice to pressure overload induced cardiac hypertrophy. We could detect specific changes in PDE3-dependent compartmentation of β-adrenergic receptor induced cAMP in non-raft membrane microdomains which were clearly different from those occurring in caveolin-rich sarcolemma. This indicates differential regulation and distinct responses of these membrane microdomains to cardiac remodeling.

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Sacubitril/valsartan ameliorates cardiac hypertrophy and preserves diastolic function in cardiac pressure overload

ESC Heart Failure ◽

10.1002/ehf2.13177 ◽

2021 ◽

Author(s):

Einar Sjaastad Nordén ◽

Bård Andre Bendiksen ◽

Henriette Andresen ◽

Kaja Knudsen Bergo ◽

Emil Knut Espe ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Diastolic Function ◽

Pressure Overload

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Effect of inhibition of glycogen synthase kinase-3 on cardiac hypertrophy during acute pressure overload

General Thoracic and Cardiovascular Surgery ◽

10.1007/s11748-009-0562-6 ◽

2010 ◽

Vol 58 (6) ◽

pp. 263-264 ◽

Cited By ~ 3

Author(s):

Fumio Yamamoto ◽

Hiroshi Yamamoto

Keyword(s):

Cardiac Hypertrophy ◽

Glycogen Synthase ◽

Pressure Overload ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3

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Ameliorative Effect of Combination of Fenofibrate and Rosiglitazone in Pressure Overload-Induced Cardiac Hypertrophy in Rats

Pharmacology ◽

10.1159/000103917 ◽

2007 ◽

Vol 80 (2-3) ◽

pp. 177-184 ◽

Cited By ~ 20

Author(s):

Madhankumar Rose ◽

Pitchai Balakumar ◽

Manjeet Singh

Keyword(s):

Cardiac Hypertrophy ◽

Pressure Overload ◽

Ameliorative Effect

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Influence of enalapril on established pressure-overload cardiac hypertrophy in low and normal renin states in female rats

Life Sciences ◽

10.1016/s0024-3205(00)00453-7 ◽

2000 ◽

Vol 66 (15) ◽

pp. 1423-1433

Author(s):

Lois Jane Heller ◽

Stephen A. Katz

Keyword(s):

Cardiac Hypertrophy ◽

Pressure Overload ◽

Female Rats

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Abstract 263: Defective Autophagy Plays a Role in the Development of Angiotensin-Induced Cardiac Hypertrophy

Circulation Research ◽

10.1161/res.111.suppl_1.a263 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Simon C Johnson ◽

Vy Nguyen ◽

Anthony Castanza ◽

Peter S Rabinovitch

Keyword(s):

Cell Death ◽

Cardiac Hypertrophy ◽

Ex Vivo ◽

Genetic Diseases ◽

Pressure Overload ◽

Small Population ◽

Tissue Imaging ◽

Unit Structure ◽

Tissue Degeneration ◽

Cell Organization

While activated autophagy is a well reported feature of cardiac disease, the exact role of autophagy in the etiology and progression of cardiac hypertrophy and dysfunction is unclear; activation of autophagy appears to play either pro-survival or pro-apoptotic functions depending on the context. Here we demonstrate that dysfunctional autophagy plays a role in the development of angiotensin II-induced cardiac hypertrophy. Using a live, ex-vivo tissue imaging technique and transgenic LC3-GFP expressing mice we found that after short term (1 week) treatment, autophagic markers accumulate in angiotensin treated mouse hearts and that in a small population of cells this accumulation reaches a critical level where normal cell organization, specifically mitochondrial localization and contractile unit structure, and tissue architecture are disrupted. These observations are reminiscent of genetic diseases associated with dysfunctional autophagy, such as inclusion body myositis, where autophagic vesicles fail to properly clear and lead to cell death and tissue degeneration. We suggest that failed autophagy contributes to pressure-overload induced hypertrophy and that the cell death associated with dramatically dysfunctional autophagy in a subset of cardiomyocytes precedes fibrosis. This work provides a clear role for dysfunctional autophagy in promoting hypertrophy and fibrosis, and supports the notion that the promotion of successful autophagy is a clinically relevant target for therapeutic intervention.

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Abstract 837: Beta1 And Beta2 Adrenergic Receptor Transgenic Mice Display Distinct MicroRNA Expression Patterns That Converge On The Hypertrophic Signature

Circulation ◽

10.1161/circ.116.suppl_16.ii_162-d ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Danish Sayed ◽

Shweta Rane ◽

Leng-Yi Chen ◽

Minzhen He ◽

Jacqueline Lypowy ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Adrenergic Receptor ◽

Mapk Pathway ◽

Expression Patterns ◽

Pressure Overload ◽

Mapk Signaling ◽

Compensatory Hypertrophy ◽

Over Expression ◽

Mrna Targets ◽

Dose Dependent

MicroRNA (miRNA) are ~22 ribonucleotides-long, with a potential to recognize multiple mRNA targets guided by sequence complimentarity. This class of molecules is functionally versatile, with the capacity to specifically inhibit translation, as well as, induce mRNA degradation, through targeting the 3′-untranslated regions. The levels of individual miRNA vary under different developmental, biological, or pathological conditions, thus, implicating them in normal and pathological cellular attributes. We have previously reported a miRNA signature that distinguishes pressure-overload compensatory hypertrophy by recapitulating the neonatal pattern. We hypothesized that this ’signature’ might aid in discriminating the underlying molecular differences in genetic models of cardiac hypertrophy, as seen in the beta1 and 2 adrenergic receptor (B1AR and B2AR) transgenic (Tg) mice. To address this, we used microarray analysis of RNA isolated from the hearts of 3 months old B1AR and B2AR mice. In general, while both mice exhibited an overlap with the hypertrophy signature including, upregulation of miR-21 and downregulation of miR-133a, miR-133b, and miR-185, the B2-AR Tg exhibited a more extensive overlap with the hypertrophy pattern, which further included upregulation of miR-199a*, miR-214, and miR-15b. To understand the functional significance of these miRNA in myocyte hypertrophy, we cloned them and their anti-sense sequences into adenoviral vectors. Significantly, over-expression miR-21 resulted in a, dose-dependent, branching (sprouting) of the cells. Computational predictions by ’TargetScanS’ identified sprouty as potential target. Subsequently, we confirmed down-regulation of sprouty by over-expression of miR-21 and vice versa. Sprouty is a known inhibitor of the Ras-MAPK signaling pathway and is, concordantly, downregulated in many forms of cancer. In the heart, sprouty has been suggested to control myocyte size and vascularization during cardiac hypertrophy. Thus, we propose that B1AR and B2AR Tg models exhibit distinct miRNA profiles that converge on that of pressure-overload cardiac hypertrophy. Moreover, the commonly over-expressed miR-21 plays a role in downregulating sprouty, an antagonist of the Ras-MAPK pathway.

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