scholarly journals Dietary carbohydrates restriction inhibits the development of cardiac hypertrophy and heart failure

2020 ◽  
Author(s):  
Michinari Nakamura ◽  
Natalija Odanovic ◽  
Yasuki Nakada ◽  
Satomi Dohi ◽  
Peiyong Zhai ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ketone Body ◽  
Control Diet ◽  
Systolic Dysfunction ◽  
Pressure Overload ◽  
Serine Threonine Kinase ◽  
Pathological Hypertrophy ◽  
Low Carbohydrate ◽  
Biochemical Analyses ◽  
Gsk 3Β

Abstract Aims A diet with modified components, such as a ketogenic low-carbohydrate (LC) diet, potentially extends longevity and healthspan. However, how an LC diet impacts on cardiac pathology during haemodynamic stress remains elusive. This study evaluated the effects of an LC diet high in either fat (Fat-LC) or protein (Pro-LC) in a mouse model of chronic hypertensive cardiac remodelling. Methods and results Wild-type mice were subjected to transverse aortic constriction, followed by feeding with the Fat-LC, the Pro-LC, or a high-carbohydrate control diet. After 4 weeks, echocardiographic, haemodynamic, histological, and biochemical analyses were performed. LC diet consumption after pressure overload inhibited the development of pathological hypertrophy and systolic dysfunction compared to the control diet. An anti-hypertrophic serine/threonine kinase, GSK-3β, was re-activated by both LC diets; however, the Fat-LC, but not the Pro-LC, diet exerted cardioprotection in GSK-3β cardiac-specific knockout mice. β-hydroxybutyrate, a major ketone body in mammals, was increased in the hearts of mice fed the Fat-LC, but not the Pro-LC, diet. In cardiomyocytes, ketone body supplementation inhibited phenylephrine-induced hypertrophy, in part by suppressing mTOR signalling. Conclusion Strict carbohydrate restriction suppresses pathological cardiac growth and heart failure after pressure overload through distinct anti-hypertrophic mechanisms elicited by supplemented macronutrients.

Abstract 744: Arrhythmogenesis in Heart Failure: Role of Interstitial Fibrosis

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Jorge E Massare ◽  
R. Haris Naseem ◽  
Jeff M Berry ◽  
Farhana Rob ◽  
Joseph A Hill
Keyword(s):  
Heart Failure ◽  
Interstitial Fibrosis ◽  
Systolic Dysfunction ◽  
Ventricular Tachyarrhythmia ◽  
Severe Heart Failure ◽  
Pressure Overload ◽  
Cellular Events ◽  
Action Potential Prolongation

Background: Sudden cardiac death due to ventricular tachyarrhythmia (VT) accounts for a large number of deaths in patients with heart failure. Several cellular events which occur during pathological remodeling of the failing ventricle are implicated in the genesis of VT, including action potential prolongation, dysregulation of intercellular coupling, and fibrosis. Interestingly, transgenic mice over-expressing constitutively active PKD (caPKD) develop severe heart failure without interstitial fibrosis, an otherwise prominent feature of the disease. The goal here was to define the role of interstitial fibrosis in the proarrhythmic phenotype of failing myocardium. Methods and Results: We performed echocardiographic, electrocardiographic, and in vivo electrophysiologic studies in 8 –10 week old caPKD mice (n=12). Similar studies were performed in mice with load-induced heart failure induced by surgical pressure overload (sTAB, n=10), a model of heart failure with prominent interstitial fibrosis. caPKD and sTAB mice showed similar degrees of ventricular dilation (LV systolic dimension caPKD 2.4±0.8 mm vs 3.0±0.9 sTAB, p=0.18) and severe systolic dysfunction (% fractional shortening caPKD 25±11 vs 28±11 sTAB, p=0.62). Yet, caPKD mice showed minimal interstitial fibrosis, comparable to unoperated controls. With the exception of ventricular refractory period, which was higher in caPKD (48±11 msec vs 36±7 TAB and 40±8 WT, p<0.05), other electrocardiographic and electrophysiologic variables were similar among the 3 groups (p=NS), including heart rate, QT duration, and mean VT threshold. As expected, VT (≥3beats) was readily inducible by programmed stimulation in sTAB mice (7/10). By contrast, VT was less inducible in caPKD mice (4/12; p=0.1 vs TAB and <0.05 vs WT), and uninducible in unoperated controls (0/12). VT was polymorphic in both models, but episodes of VT were both slower (VT cycle length caPKD 58±4.0 msec vs 48±1 sTAB, p=0.016) and longer in caPKD mice (caPKD 1.8±0.7 sec vs 0.47±0.3 sTAB, p=0.038). Conclusion: Interstitial fibrosis contributes to the inducibility, maintenance, and rate of VT in heart failure. These findings highlight the importance of anti-remodeling therapies known to target fibrosis in heart disease.

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.

Ketone Body Metabolism Attenuates Oxidative Stress and Cardiac Remodeling in Pressure Overload Heart Failure

2014 ◽  
Vol 20 (10) ◽  
pp. S204
Author(s):  
Motoki Uchihashi ◽  
Atsushi Hoshino ◽  
Makoto Ariyoshi ◽  
Shuhei Tateishi ◽  
Kazunori Ono ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cardiac Remodeling ◽  
Ketone Body ◽  
Pressure Overload ◽  
Ketone Body Metabolism

Abstract 159: Ablation of the Hypertension Candidate Gene ATP2B1 Leads To Deficient Calcium Cycling, Systolic Dysfunction and Heart Failure Following Pressure Overload

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Nicholas P Stafford ◽  
Min Zi ◽  
Ludwig Neyses ◽  
Elizabeth J Cartwright
Keyword(s):  
Heart Failure ◽  
Systolic Dysfunction ◽  
Pressure Overload ◽  
Early Response ◽  
Left Ventricular ◽  
Calcium Handling ◽  
Calcium Cycling ◽  
Lung Weight ◽  
Hypertrophic Growth ◽  
Ventricular Elastance

Mutations in ATP2B1 encoding the ubiquitous calcium extrusion pump Plasma Membrane Calcium ATPase 1 (PMCA1) have recently identified it as having the strongest association of any gene to hypertension, yet the role of PMCA1 in the pressure-overloaded heart is not known. To investigate this we generated a novel mouse line carrying cardiomyocyte-specific deletion of PMCA1 (PMCA1 cko ) and challenged them with transverse aortic constriction (TAC) alongside littermate ‘floxed’ controls (PMCA1 f/f ). After two weeks, echocardiographic analysis revealed signs of systolic dysfunction and left ventricular (LV) dilation in PMCA1 cko hearts as evidenced by reduced fractional shortening and increased diastolic diameter (both p<0.05), whilst function in PMCA1 f/f TAC controls remained preserved. This was accompanied by an increase in normalised lung weight in PMCA1 cko mice compared to sham operated and TAC controls (p<0.05) indicative of pulmonary congestion and a progression into LV failure, despite comparable hypertrophic growth amongst the two TAC cohorts. Hemodynamic analysis following LV catheterisation revealed contractility, as measured by left ventricular elastance (E es ), to be increased in controls after TAC (PMCA1 f/f TAC 12.69 ± 1.63 vs sham 7.02 ± 1.11 mmHg/μl, p<0.05), a change which was not reciprocated in knockout hearts (PMCA1 cko TAC 7.70 ± 1.19 vs sham 7.22 ± 1.55 mmHg/μl). To examine whether altered calcium handling could be the underlying cause of the observed phenotype, cardiomyocytes were isolated following one week TAC and loaded with Indo-1, prior to the onset of failure in PMCA1 cko hearts. Compatible with an increase in E es , systolic calcium levels were higher in PMCA1 f/f myocytes following pressure overload compared to sham controls (p<0.05), whilst PMCA1 cko TAC myocytes displayed equivalent peak calcium levels to their respective sham controls. These results suggest that PMCA1 may play a necessary role in enhancing calcium cycling during the early response to pressure overload, and that disrupting this gene may increase the susceptibility to heart failure under these conditions. This may provide first evidence of a novel genetic basis for the development of heart failure in a proportion of hypertensive patients.

Abstract 299: Simultaneous Cardiac And Adrenal Small Molecule GPCR-Gβ? Inhibition Halts The Progression Of Pressure Overload Heart Failure

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Fadia A Kamal ◽  
Deanne Mickelsen ◽  
Jacob Moalem ◽  
Stephen R Hammes ◽  
Alan V Smrcka ◽  
...  
Keyword(s):  
Heart Failure ◽  
Adrenal Gland ◽  
Small Molecule ◽  
Adrenal Glands ◽  
Pressure Overload ◽  
Salient Feature ◽  
Therapeutic Benefit ◽  
Pharmacologic Therapy ◽  
Inhibitory Function ◽  
Gsk 3Β

Heart failure (HF) is a progressive disease with rapidly increasing rates of morbidity and mortality. Elevated sympathetic nervous system activity, a salient feature of HF progression, leads to pathologic attenuation and desensitization of β-adrenergic receptors (β-ARs) due in part to Gβγ-mediated signaling. In the current study, we assessed the hypothesis that the small molecule Gβγ inhibitor “gallein” is salutary in treating pre-existing HF in a clinically relevant model (pressure-overload HF model of mouse transverse aortic constriction (TAC)) by simultaneously normalizing adrenergic receptor signaling in the heart and the adrenal gland. Four weeks post-TAC, mice received daily i.p. injections of vehicle or gallein for eight weeks (n=6-8 per group). Serial echocardiography was performed through out the study. At the end of the experiment, hemodynamic studies were performed, mice were sacrificed, blood, heart, and adrenal glands were harvested for further analysis. Gallein treatment improved survival and cardiac function and reduced cardiac hypertrophy, remodeling, and fetal genes expression in TAC mice. On the molecular level, gallein recovered membrane β-AR density and attenuated GRK2-PI3Kγ membrane recruitment, and Akt-GSK-3β signaling in TAC hearts. A salutary adrenal effect of gallein was obtained in cultured mice adrenal glands and human pheochromocytoma tissue (n=3), where direct gallein treatment restored α2-AR feedback inhibitory function and concurrently reduced catecholamine production. Moreover, gallein treatment attenuated adrenal hypertrophy in TAC mice and downregulated tyrosine hydroxylase and chromogranin A protein expression in adrenal glands from TAC mice and cultured pheochromocytoma tissue as well. In summary, our data suggest gallein as a systemic pharmacologic therapy with substantial therapeutic benefit in HF by simultaneously normalizing pathologic Gβγ-GRK2 signaling and recovering AR signaling in both the heart and the adrenal gland. In the heart, gallein mediated attenuation of cardiac remodeling probably involves inhibiting GRK2-PI3K-Akt signaling. Our data also suggest a role for small molecule Gβγ inhibition in other diseases of elevated catecholamine release, such as pheochromocytoma.

Chronic Rapamycin Therapy Ameliorates Hypertrophy and Systolic Dysfunction in Severe Chronic Heart Failure Due to Pressure Overload

2010 ◽  
Vol 16 (8) ◽  
pp. S9
Author(s):  
Kalkidan Bishu ◽  
Selma Mohammed ◽  
Tomohito Ohtani ◽  
Sudhir Kushwaha ◽  
Xiaolei Xu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Systolic Dysfunction ◽  
Pressure Overload ◽  
Severe Chronic Heart Failure

scholarly journals Cardiac 12/15 lipoxygenase–induced inflammation is involved in heart failure

2009 ◽  
Vol 206 (7) ◽  
pp. 1565-1574 ◽  
Author(s):  
Yosuke Kayama ◽  
Tohru Minamino ◽  
Haruhiro Toko ◽  
Masaya Sakamoto ◽  
Ippei Shimizu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Systolic Dysfunction ◽  
Pressure Overload ◽  
Eicosatetraenoic Acid ◽  
Wild Type ◽  
Monocyte Chemoattractant Protein 1 ◽  
Novel Target

To identify a novel target for the treatment of heart failure, we examined gene expression in the failing heart. Among the genes analyzed, Alox15 encoding the protein 12/15 lipoxygenase (LOX) was markedly up-regulated in heart failure. To determine whether increased expression of 12/15-LOX causes heart failure, we established transgenic mice that overexpressed 12/15-LOX in cardiomyocytes. Echocardiography showed that Alox15 transgenic mice developed systolic dysfunction. Cardiac fibrosis increased in Alox15 transgenic mice with advancing age and was associated with the infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein 1 (MCP-1) was up-regulated in Alox15 transgenic mice compared with wild-type mice. Treatment with 12-hydroxy-eicosatetraenoic acid, a major metabolite of 12/15-LOX, increased MCP-1 expression in cardiac fibroblasts and endothelial cells but not in cardiomyocytes. Inhibition of MCP-1 reduced the infiltration of macrophages into the myocardium and prevented both systolic dysfunction and cardiac fibrosis in Alox15 transgenic mice. Likewise, disruption of 12/15-LOX significantly reduced cardiac MCP-1 expression and macrophage infiltration, thereby improving systolic dysfunction induced by chronic pressure overload. Our results suggest that cardiac 12/15-LOX is involved in the development of heart failure and that inhibition of 12/15-LOX could be a novel treatment for this condition.

scholarly journals Excessive O - GlcNAcylation causes heart failure and sudden death

2020 ◽  
Author(s):  
Priya Umapathi ◽  
Partha S. Banerjee ◽  
Natasha E. Zachara ◽  
Neha Abrol ◽  
Qinchuan Wang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mouse Models ◽  
Complex I ◽  
Pressure Overload ◽  
Premature Death ◽  
List Type ◽  
Mitochondrial Complex ◽  
Pathological Hypertrophy ◽  
Complex I Activity ◽  
Genetic Mouse Models

AbstractBackgroundHeart failure is a leading cause of death worldwide and is associated with the rising prevalence of obesity, hypertension and diabetes. O-GlcNAcylation, a post-translational modification of intracellular proteins, serves as a potent transducer of cellular stress. Failing myocardium is marked by increased O-GlcNAcylation, but it is unknown if excessive O-GlcNAcylation contributes to cardiomyopathy and heart failure. The total levels of O-GlcNAcylation are determined by nutrient and metabolic flux, in addition to the net activity of two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA).MethodsWe developed two new transgenic mouse models with myocardial overexpression of OGT and OGA to control O-GlcNAclyation independent of pathological stress.ResultsWe found that OGT transgenic hearts showed increased O-GlcNAcylation, and developed severe dilated cardiomyopathy, ventricular arrhythmias and premature death. In contrast, OGA transgenic hearts had O-GlcNAcylation and cardiac function similar to wild type littermate controls. However, OGA trangenic hearts were resistant to pathological stress induced by pressure overload and had attenuated myocardial O-GlcNAcylation levels, decreased pathological hypertrophy and improved systolic function. Interbreeding OGT with OGA transgenic mice rescued cardiomyopathy and premature death despite persistant elevation of myocardial OGT. Transcriptomic and functional studies revealed disrupted mitochondrial energetics with impairment of complex I activity in hearts from OGT transgenic mice. Complex I activity was rescued by OGA transgenic interbreeding, suggesting an important role for mitochondrial complex I in O-GlcNAc mediated cardiac pathology.ConclusionsOur data provide evidence that excessive O-GlcNAcylation causes cardiomyopathy, at least in part, due to defective energetics. Enhanced OGA activity is well tolerated and attenuation of O-GlcNAcylation is an effective therapy against pressure overload induced heart failure. Attenuation of excessive O-GlcNAcylation may represent a novel therapeutic approach for cardiomyopathy.Clinical PerspectiveWhat is new?Cardiomyopathy from diverse causes is marked by increased O-GlcNAcylation. Here we provide new genetic mouse models to control myocardial O-GlcNAcylation independent of pathological stress.Genetically increased myocardial O-GlcNAcylation causes progressive dilated cardiomyopathy and premature death, while genetic reduction of myocardial O-GlcNAcylation is protective against pathological hypertrophy caused by transaortic banding.Excessive myocardial O-GlcNAcylation decreases activity and expression of mitochondrial complex I.What are the clinical implications?Increased myocardial O-GlcNAcylation has been shown to be associated with a diverse range of clinical heart failure including aortic stenosis, hypertension, ischemia and diabetes.Using novel genetic mouse models we have provided new proof of concept data that excessive O-GlcNAcylation is sufficient to cause cardiomyopathy.We have shown myocardial over-expression of O-GlcNAcase, an enzyme that reverses O-GlcNAcylation, is well tolerated at baseline, and improves myocardial responses to pathological stress.Our findings suggest reversing excessive myocardial O-GlcNAcylation could benefit diverse etiologies of heart failure.

scholarly journals Rubicon-regulated beta-1 adrenergic receptor recycling protects the heart from pressure overload

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Yasuhiro Akazawa ◽  
Manabu Taneike ◽  
Hiromichi Ueda ◽  
Rika Kitazume-Taneike ◽  
Tomokazu Murakawa ◽  
...  
Keyword(s):  
Heart Failure ◽  
Adrenergic Receptor ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Pressure Overload ◽  
Developed Countries ◽  
Left Ventricular ◽  
Negative Regulator ◽  
High Morbidity ◽  
Deficient Mice

AbstractHeart failure has high morbidity and mortality in the developed countries. Autophagy is important for the quality control of proteins and organelles in the heart. Rubicon (Run domain Beclin-1-interacting and cysteine-rich domain-containing protein) has been identified as a potent negative regulator of autophagy and endolysosomal trafficking. The aim of this study was to investigate the in vivo role of Rubicon-mediated autophagy and endosomal trafficking in the heart. We generated cardiomyocyte-specific Rubicon-deficient mice and subjected the mice to pressure overload by means of transverse aortic constriction. Rubicon-deficient mice showed heart failure with left ventricular dilatation, systolic dysfunction and lung congestion one week after pressure overload. While autophagic activity was unchanged, the protein amount of beta-1 adrenergic receptor was decreased in the pressure-overloaded Rubicon-deficient hearts. The increases in heart rate and systolic function by beta-1 adrenergic stimulation were significantly attenuated in pressure-overloaded Rubicon-deficient hearts. In isolated rat neonatal cardiomyocytes, the downregulation of the receptor by beta-1 adrenergic agonist was accelerated by knockdown of Rubicon through the inhibition of recycling of the receptor. Taken together, Rubicon protects the heart from pressure overload. Rubicon maintains the intracellular recycling of beta-1 adrenergic receptor, which might contribute to its cardioprotective effect.

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