scholarly journals Excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents

2010 ◽  
Vol 120 (5) ◽  
pp. 1506-1514 ◽  
Author(s):  
Ippei Shimizu ◽  
Tohru Minamino ◽  
Haruhiro Toko ◽  
Sho Okada ◽  
Hiroyuki Ikeda ◽  
...  
Keyword(s):  
Insulin Signaling ◽  
Systolic Dysfunction ◽  
Pressure Overload

Minimally invasive aortic banding in mice: effects of altered cardiomyocyte insulin signaling during pressure overload

2003 ◽  
Vol 285 (3) ◽  
pp. H1261-H1269 ◽  
Author(s):  
Ping Hu ◽  
Dongfang Zhang ◽  
LeAnne Swenson ◽  
Gopa Chakrabarti ◽  
E. Dale Abel ◽  
...  
Keyword(s):  
Minimally Invasive ◽  
Insulin Signaling ◽  
Systolic Pressure ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Tissue Growth ◽  
Cardiac Response ◽  
Heart Weight ◽  
Surgical Morbidity ◽  
Aortic Banding

We developed a minimally invasive method for producing left ventricular (LV) pressure overload in mice. With the use of this technique, we quickly and reproducibly banded the transverse aorta with low surgical morbidity and mortality. Minimally invasive transverse aortic banding (MTAB) acutely and chronically increased LV systolic pressure, increased heart weight-to-body weight ratio, and induced myocardial fibrosis. We used this technique to determine whether reduced insulin signaling in the heart altered the cardiac response to pressure overload. Mice with cardiac myocyte-restricted knockout of the insulin receptor (CIRKO) have smaller hearts than wild-type (WT) controls. Four weeks after MTAB, WT and CIRKO mice had comparably increased LV systolic pressure, increased cardiac mass, and induction of mRNA for β-myosin heavy chain and atrial natriuretic factor. However, CIRKO hearts were more dilated, had depressed LV systolic function by echocardiography, and had greater interstitial fibrosis than WT mice. Expression of connective tissue growth factor was increased in banded CIRKO hearts compared with WT hearts. Thus lack of insulin signaling in the heart accelerates the transition to a more decompensated state during cardiac pressure overload. The use of the MTAB approach should facilitate the study of the pathophysiology and treatment of pressure-overload hypertrophy.

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.

Phospholamban Inhibition by a Single Dose of Locked Nucleic Acid Antisense Oligonucleotide Improves Cardiac Contractility in Pressure Overload-Induced Systolic Dysfunction in Mice

2016 ◽  
Vol 22 (3) ◽  
pp. 273-282 ◽  
Author(s):  
Hirofumi Morihara ◽  
Tsuyoshi Yamamoto ◽  
Harunori Oiwa ◽  
Kota Tonegawa ◽  
Daisuke Tsuchiyama ◽  
...  
Keyword(s):  
Single Dose ◽  
Nucleic Acid ◽  
Cardiac Dysfunction ◽  
Systolic Dysfunction ◽  
Pressure Overload ◽  
Locked Nucleic Acid ◽  
Novel Therapy ◽  
Medical Needs ◽  
Promising Tool ◽  
Dose Injection

Background: Phospholamban (PLN) inhibition enhances calcium cycling and is a potential novel therapy for heart failure (HF). Antisense oligonucleotides (ASOs) are a promising tool for unmet medical needs. Nonviral vector use of locked nucleic acid (LNA)-modified ASOs (LNA-ASOs), which shows strong binding to target RNAs and is resistant to nuclease, is considered to have a potential for use in novel therapeutics in the next decades. Thus, the efficacy of a single-dose injection of LNA-ASO for cardiac disease needs to be elucidated. We assessed the therapeutic efficacy of a single-dose LNA-ASO injection targeting PLN in pressure overload-induced cardiac dysfunction. Methods and Results: Mice intravenously injected with Cy3-labeled LNA-ASO displayed Cy3 fluorescence in the liver and heart 24 hours after injection. Subsequently, male C57BL/6 mice were subjected to sham or transverse aortic constriction surgery; after 3 weeks, these were treated with PLN-targeting LNA-ASO (0.3 mg/kg) or scrambled LNA-ASO. Cardiac function was measured by echocardiography before and 1 week after injection. Phospholamban-targeting LNA-ASO treatment significantly improved fractional shortening (FS) by 6.5%, whereas administration of the scrambled LNA-ASO decreased FS by 4.0%. Conclusion: Our study revealed that a single-dose injection of PLN-targeting LNA-ASO improved contractility in pressure overload-induced cardiac dysfunction, suggesting that LNA-ASO is a promising tool for hypertensive HF treatment.

scholarly journals Orai1 Channel Inhibition Preserves Left Ventricular Systolic Function and Normal Ca 2+ Handling After Pressure Overload

Circulation ◽  
2020 ◽  
Vol 141 (3) ◽  
pp. 199-216 ◽  
Author(s):  
Fiona Bartoli ◽  
Marc A. Bailey ◽  
Baptiste Rode ◽  
Philippe Mateo ◽  
Fabrice Antigny ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Pressure Overload ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Specific Expression ◽  
Channel Inhibition

Background: Orai1 is a critical ion channel subunit, best recognized as a mediator of store-operated Ca 2+ entry (SOCE) in nonexcitable cells. SOCE has recently emerged as a key contributor of cardiac hypertrophy and heart failure but the relevance of Orai1 is still unclear. Methods: To test the role of these Orai1 channels in the cardiac pathophysiology, a transgenic mouse was generated with cardiomyocyte-specific expression of an ion pore-disruptive Orai1 R91W mutant (C-dnO1). Synthetic chemistry and channel screening strategies were used to develop 4-(2,5-dimethoxyphenyl)-N-[(pyridin-4-yl)methyl]aniline (hereafter referred to as JPIII), a small-molecule Orai1 channel inhibitor suitable for in vivo delivery. Results: Adult mice subjected to transverse aortic constriction (TAC) developed cardiac hypertrophy and reduced ventricular function associated with increased Orai1 expression and Orai1-dependent SOCE (assessed by Mn 2+ influx). C-dnO1 mice displayed normal cardiac electromechanical function and cellular excitation-contraction coupling despite reduced Orai1-dependent SOCE. Five weeks after TAC, C-dnO1 mice were protected from systolic dysfunction (assessed by preserved left ventricular fractional shortening and ejection fraction) even if increased cardiac mass and prohypertrophic markers induction were observed. This is correlated with a protection from TAC-induced cellular Ca 2+ signaling alterations (increased SOCE, decreased [Ca 2+ ] i transients amplitude and decay rate, lower SR Ca 2+ load and depressed cellular contractility) and SERCA2a downregulation in ventricular cardiomyocytes from C-dnO1 mice, associated with blunted Pyk2 signaling. There was also less fibrosis in heart sections from C-dnO1 mice after TAC. Moreover, 3 weeks treatment with JPIII following 5 weeks of TAC confirmed the translational relevance of an Orai1 inhibition strategy during hypertrophic insult. Conclusions: The findings suggest a key role of cardiac Orai1 channels and the potential for Orai1 channel inhibitors as inotropic therapies for maintaining contractility reserve after hypertrophic stress.

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.

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