The Mechanism of High-Output Cardiac Hypertrophy Arising From Potassium Channel Gain-of-Function in Cantú Syndrome

Abstract Dramatic cardiomegaly arising from gain-of-function (GoF) mutations in the ATP-sensitive potassium (KATP) channels genes, ABCC9 and KCNJ8, is a characteristic feature of Cantú syndrome (CS). How potassium channel over-activity results in cardiac hypertrophy, as well as the long-term consequences of cardiovascular remodeling in CS, is unknown. Using genome-edited mouse models of CS, we therefore sought to dissect the pathophysiological mechanisms linking KATP channel GoF to cardiac remodeling. We demonstrate that chronic reduction of systemic vascular resistance in CS is accompanied by elevated renin–angiotensin signaling, which drives cardiac enlargement and blood volume expansion. Cardiac enlargement in CS results in elevation of basal cardiac output, which is preserved in aging. However, the cardiac remodeling includes altered gene expression patterns that are associated with pathological hypertrophy and are accompanied by decreased exercise tolerance, suggestive of reduced cardiac reserve. Our results identify a high-output cardiac hypertrophy phenotype in CS which is etiologically and mechanistically distinct from other myocardial hypertrophies, and which exhibits key features of high-output heart failure (HOHF). We propose that CS is a genetically-defined HOHF disorder and that decreased vascular smooth muscle excitability is a novel mechanism for HOHF pathogenesis.

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The Pathophysiology of Cardiac Abnormalities in Cantu Syndrome: Perspective on “The Mechanism of High-Output Cardiac Hypertrophy Arising From Potassium Channel Gain-of-Function in Cantú Syndrome”

Function ◽

10.1093/function/zqaa005 ◽

2020 ◽

Vol 1 (1) ◽

Author(s):

Qadeer Aziz ◽

Andrew Tinker

Keyword(s):

Cardiac Hypertrophy ◽

Potassium Channel ◽

Channel Gain ◽

Gain Of Function ◽

Cardiac Abnormalities ◽

High Output

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A multi-network comparative analysis of transcriptome and translatome in cardiac remodeling

10.1101/2020.07.01.181743 ◽

2020 ◽

Author(s):

Etienne Boileau ◽

Shirin Doroudgar ◽

Eva Riechert ◽

Lonny Jürgensen ◽

Thanh Cao Ho ◽

...

Keyword(s):

Comparative Analysis ◽

Cardiac Hypertrophy ◽

Cardiac Remodeling ◽

Gene Networks ◽

Regulatory Networks ◽

Functional Modules ◽

Hub Genes ◽

Pathological Cardiac Hypertrophy ◽

Altered Gene

Our understanding of the transition from physiological to pathological cardiac hypertrophy remains elusive and largely based on reductionist hypotheses. Here, we profiled the translatomes of 15 mouse hearts to provide a molecular blueprint of altered gene networks in early cardiac remodeling. Using co-expression analysis, we reveal how sub-networks are orchestrated into functional modules associated with pathological phenotypes. We show how transcriptome networks are only partially reproducible at the translatome level. We find unappreciated hub genes and genes in the transcriptional network that were rewired in the translational network, and associated with semantically different subsets of enriched functional terms, providing novel insights into the complexity of the organization of in vivo cardiac regulatory networks.

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Chronic captopril and losartan (DuP 753) administration in rats with high-output heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1992.263.3.h833 ◽

1992 ◽

Vol 263 (3) ◽

pp. H833-H840 ◽

Cited By ~ 4

Author(s):

G. Qing ◽

R. Garcia

Keyword(s):

Heart Failure ◽

Cardiac Hypertrophy ◽

Renin Angiotensin System ◽

Left Ventricular ◽

Right Atrial ◽

Angiotensin Converting Enzyme Inhibition ◽

Arterial Blood ◽

High Output Heart Failure ◽

Regression Of Cardiac Hypertrophy ◽

High Output

We investigated the role of atrial natriuretic factor (ANF) and the renin-angiotensin system as well as the effects of losartan in rats with aortocaval (AC) shunts. Right atrial and left ventricular end-diastolic pressures (LVEDP) were higher and mean arterial blood pressure (MAP) was lower in AC shunt animals than in their controls. AC shunt rats presented marked cardiac hypertrophy, decreased right atrial ANF concentration, and increased ventricular ANF content and concentration. Plasma ANF levels were elevated, and hematocrit was lower in AC shunt animals than in controls. Captopril or losartan treatment decreased MAP and returned LVEDP to sham-operated control values. A clear regression of cardiac hypertrophy was evident in both treated AC shunt groups, with plasma ANF levels tending to follow those in sham-operated rats. Plasma COOH-terminal ANF levels were decreased and urinary volume and hematocrit were increased in losartan-treated AC shunt animals. We conclude that chronic angiotensin converting enzyme inhibition and angiotension II receptor antagonism improved hemodynamic conditions, diminished water retention, reversed cardiac hypertrophy, and restored plasma and tissue ANF to more “normal” levels in rats with moderate high-output heart failure.

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Abstract 16482: Cardiac Remodeling During Pregnancy With Challenge: A Prologue of Pathological Remodeling

Circulation ◽

10.1161/circ.142.suppl_3.16482 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Yijun Yang ◽

Justin Kurian ◽

Giana Schena ◽

Jaslyn Johnson ◽

Hajime KUBO ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Cardiac Remodeling ◽

Expression Patterns ◽

Gene Activation ◽

Normal Pregnancy ◽

Heart Weight ◽

Cardiomyocyte Hypertrophy ◽

Childbearing Age ◽

Life Style Changes ◽

Pathological Remodeling

Introduction: Life-style changes in the past decades have led to an increased incidence of metabolic syndrome (MetS), obesity and hypertension in women of childbearing age. These comorbidities are known to predispose individuals to adverse cardiovascular events. There is also evidence that cardiovascular complications during pregnancy may link to future heart diseases. During normal pregnancy, the heart undergoes physiological hypertrophy without fibrosis or fetal gene activation. However, recent study showed extremely obese women have increased cardiac hypertrophy and more frequent diastolic dysfunction at term. The objective of this research was to determine if MetS modifies the cardiac remodeling that takes place during pregnancy. Hypothesis: MetS during pregnancy induces pathological rather than physiological cardiac remodeling. Methods and Results: We performed long-term feeding of high fat (45%kcal) diet (HFD) in C57BL/6J female mice to establish a model of MetS, which showed increased body weight, impaired glucose tolerance and dyslipidemia compared to normal chow, resembling the features of human MetS. After pregnancy, HFD fed mice showed higher heart weight and ECHO-derived LV mass compared with Ctrl. Pregnant mice with MetS had signs of pathological cardiac remodeling, such as cardiomyocyte hypertrophy, fetal gene activation and interstitial fibrosis. At the transcriptome level, pregnancy in HFD fed mice lead to distinct gene expression patterns compared to normal pregnancy, with enrichment in genes involved in cardiac hypertrophy, oxidative stress and fibroblast activation that likely underly the adverse remodeling. Moreover, when animals were stressed with Angiotensin/phenylephrine infusion, MetS postpartum hearts had more severe cardiac hypertrophy, with overt concentric remodeling and increased fibrosis accumulation compared with nulliparous females Conclusions: MetS can induce maladaptive cardiac remodeling during pregnancy and exacerbate pathological remodeling in the postpartum heart.

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Inhibition of the water channel aquaporin-1 prevents myocardial remodeling by blocking the transmembrane transport of hydrogen peroxide

European Heart Journal ◽

10.1093/ehjci/ehaa946.3665 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

V Montiel ◽

R Bella ◽

L Michel ◽

E Robinson ◽

J.C Jonas ◽

...

Keyword(s):

Hydrogen Peroxide ◽

Cardiac Hypertrophy ◽

Cardiac Myocytes ◽

Cardiac Remodeling ◽

Cardiac Myocyte ◽

Water Channel ◽

Transmembrane Transport ◽

Funding Source ◽

Water Pore

Abstract Background Pathological remodeling of the myocardium has long been known to involve oxidant signaling, but so far, strategies using systemic anti-oxidants have generally failed to prevent it. Aquaporins are a family of transmembrane water channels with thirteen isoforms currently known. Some isoforms have been implicated in oxidant signaling. AQP1 is the most abundant aquaporin in cardiovascular tissues but its specific role in cardiac remodeling remains unknown. Purpose We tested the role of AQP1 as a key regulator of oxidant-mediated cardiac remodeling amenable to targeted pharmacological therapy. Methods We used mice with genetic deletion of Aqp1 (and wild-type littermate), as well as primary isolates from the same mice and human iPSC/Engineered Heart Tissue to test the role of AQP1 in pro-hypertrophic signaling. Human cardiac myocyte-specific (PCM1+) expression of AQP's and genes involved in hypertrophic remodeling was studied by RNAseq and bioinformatic GO pathway analysis. Results RNA sequencing from human cardiac myocytes revealed that the archetypal AQP1 is a major isoform. AQP1 expression correlates with the severity of hypertrophic remodeling in patients with aortic stenosis. The AQP1 channel was detected at the plasma membrane of human and mouse cardiac myocytes from hypertrophic hearts, where it colocalizes with the NADPH oxidase-2 (NOX2) and caveolin-3. We show that hydrogen peroxide (H2O2), produced extracellularly, is necessary for the hypertrophic response of isolated cardiac myocytes and that AQP1 facilitates the transmembrane transport of H2O2 through its water pore, resulting in activation of oxidant-sensitive kinases in cardiac myocytes. Structural analysis of the amino acid residues lining the water pore of AQP1 supports its permeation by H2O2. Deletion of Aqp1 or selective blockade of AQP1 intra-subunit pore (with Bacopaside II) inhibits H2O2 transport in mouse and human cells and rescues the myocyte hypertrophy in human induced pluripotent stem cell-derived engineered heart muscle. This protective effect is due to loss of transmembrane transport of H2O2, but not water, through the intra-subunit pore of AQP1. Treatment of mice with clinically-approved Bacopaside extract (CDRI08) inhibitor of AQP1 attenuates cardiac hypertrophy and fibrosis. Conclusion We provide the first demonstration that AQP1 functions as an aqua-peroxiporin in primary rodent and human cardiac parenchymal cells. We show that cardiac hypertrophy is mediated by the transmembrane transport of H2O2 through the AQP1 water channel. Our studies open the way to complement the therapeutic armamentarium with specific blockers of AQP1 for the prevention of adverse remodeling in many cardiovascular diseases leading to heart failure. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): FRS-FNRS, Welbio

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

Antioxidants ◽

10.3390/antiox10060931 ◽

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.

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