scholarly journals Circadian mutant mice with obesity and metabolic syndrome are resilient to cardiovascular disease

2020 ◽  
Vol 319 (5) ◽  
pp. H1097-H1111
Author(s):  
Cristine J. Reitz ◽  
Faisal J. Alibhai ◽  
Bruna Gazzi de Lima-Seolin ◽  
Ashley Nemec-Bakk ◽  
Neelam Khaper ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Metabolic Syndrome ◽  
Cardiac Dysfunction ◽  
High Fat Diet ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Metabolic Dysfunction ◽  
Wild Type ◽  
High Fat

We examined whether obesity and metabolic syndrome underlie the development of cardiac dysfunction in circadian mutant ClockΔ19/Δ19 mice. Surprisingly, we demonstrate that although ClockΔ19/Δ19 mice develop metabolic dysfunction, they are protected from cardiac hypertrophy, left ventricular remodeling, and diastolic dysfunction, in contrast to wild-type controls, even when challenged with a chronic high-fat diet. These findings shed new light on the circadian regulation of oxidative stress pathways that can mediate resilience to cardiovascular disease.

Abstract 394: Posttranslational Modification Of Klf5 Mediates Metabolic Dysfunction And Vascular Disease In Metabolic Syndrome

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Yumiko Oishi ◽  
Ichiro Manabe ◽  
Kazuyuki Tobe ◽  
Takashi Kadowaki ◽  
Ryozo Nagai
Keyword(s):  
Skeletal Muscle ◽  
Metabolic Syndrome ◽  
Energy Expenditure ◽  
Posttranslational Modifications ◽  
High Fat Diet ◽  
Metabolic Diseases ◽  
C2c12 Myotubes ◽  
Metabolic Dysfunction ◽  
High Fat ◽  
Increased Risk

We have previously shown that a zinc finger transcription factor, Krüppel-like factor 5 (KLF5), plays an important role in pathogenesis of cardiovascular diseases, such as atherosclerosis. KLF5 heterozygous knockout ( KLF5 +/ − ) mice exhibited much less neointima formation, cardiac hypertrophy and fibrosis. We also found that expression of KLF5 correlated with a higher incidence of restenosis following PCI and the SNP located within the KLF5 promoter was associated with an increased risk of hypertension in man. Interestingly, KLF5 is also expressed in metabolic tissues such as adipose tissue, skeletal muscle, and pancreatic β-cells. Thus, we hypothesized that KLF5 might play a role in metabolic diseases. To test this, KLF5 +/ − mice were fed with high-fat diet. Although KLF5 +/ − mice ate more food than wild-type littermates, they were resistant to high-fat diet-induced obesity and protected from dyslipidemia, glucose intolerance and hepatic steatosis, indicating that KLF5 + /− mice were less susceptible to metabolic syndrome. The systemic O 2 consumption and expression of genes involved in energy expenditure in skeletal muscle were increased in KLF5 + /− mice, demonstrating enhanced energy expenditure, which partly explains the phenotype. Knocking down KLF5 by siRNA increased expression levels of UCP2/3 and CPT-1b in C2C12 myotubes, suggesting that KLF5 may inhibit energy expenditure-related genes. Chromatin immunoprecipitation and coimmunoprecipitation assays showed that KLF5 interacted with corepressors, such as SMRT and NCoR, and strongly inhibited the UCP and CPT-1b promoters. We found that this inhibitory activity of KLF5 depended on its SUMOylation. When KLF5 was deSUMOylated, it activated the promoters. These data demonstrate that KLF5 acts as a molecular switch for energy expenditure and the posttranslational modifications of KLF5 including SUMOylation turns on/off the switch function of KLF5. Given that KLF5 also controls tissue remodeling in response to external stress, KLF5 may mediate metabolic dysfunction and atherosclerosis in metabolic syndrome. Our findings also suggest that the posttranscriptional modification of KLF5 is an attractive novel therapeutic target.

Exercise training prevents the development of cardiac dysfunction in the low-dose streptozotocin diabetic rats fed a high-fat diet

2013 ◽  
Vol 91 (1) ◽  
pp. 80-89 ◽  
Author(s):  
Riley A. Epp ◽  
Shanel E. Susser ◽  
Marc P. Morissette ◽  
D. Scott Kehler ◽  
Davinder S. Jassal ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Exercise Training ◽  
Protein Content ◽  
Cardiac Dysfunction ◽  
High Fat Diet ◽  
Low Dose ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
High Fat ◽  
Altered Expression

This study tested the hypothesis that exercise training would prevent the development of diabetes-induced cardiac dysfunction and altered expression of sarcoplasmic reticulum Ca2 +-transport proteins in the low-dose streptozotocin-induced diabetic rats fed a high-fat diet (HFD+STZ). Male Sprague–Dawley rats (4 weeks old; 125–150 g) were made diabetic using a high-fat diet (40% fat, w/w) and a low-dose of streptozotocin (35 mg·(kg body mass)–1) by intravenous injection. Diabetic animals were divided among a sedentary group (Sed+HFD+STZ) or an exercise-trained group (Ex+HFD+STZ) that accumulated 3554 ± 338 m·day–1 of voluntary wheel running (mean ± SE). Sedentary animals fed a low-fat diet served as the control (Sed+LFD). Oral glucose tolerance was impaired in the sedentary diabetic group (1179 ± 29; area under the curve (a.u.c.)) compared with that in the sedentary control animals (1447 ± 42 a.u.c.). Although left ventricular systolic function was unchanged by diabetes, impaired E/A ratios (i.e., diastolic function) and rates of pressure decay (–dP/dt) indicated the presence of diastolic dysfunction. Diabetes also reduced SERCA2a protein content and maximal SERCA2a activity (Vmax) by 21% and 32%, respectively. In contrast, the change in each parameter was attenuated by exercise training. Based on these data, it appears that exercise training prevented the development of diabetic cardiomyopathy and the dysregulation of sarcoplasmic reticulum protein content in an inducible animal model of type 2 diabetes.

scholarly journals Changes of morphofunctional state of cardiovascular system in adolescents with metabolic syndrome manifestations

2021 ◽  
Vol 12 (1) ◽  
pp. 21-30
Author(s):  
Natalya V. Gonchar ◽  
Аnzhela А. Аvakyan ◽  
Svetlana N. Chuprova ◽  
Nikolay V. Slizovskiy
Keyword(s):  
Metabolic Syndrome ◽  
Arterial Hypertension ◽  
Cardiovascular System ◽  
Autonomic Dysfunction ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Holter Monitoring ◽  
Left Ventricular ◽  
Diagnostic Methods ◽  
Group 2

The results of investigation of features of morphofunctional state of cardiovascular system in adolescents with manifestations of metabolic syndrome depending on presence of hyperuricemia are presented. In the cardiorheumatology department of the hospital, 34 adolescent patients were observed. Criteria for inclusion in the study: the presence of increased blood pressure levels, increased body mass index values. Depending on serum uric acid levels, patients were divided into two groups: group 1 patients without hyperuricemia (n = 18) and group 2 patients with hyperuricemia (n = 16). Functional diagnostic methods were used: standard 12-channel electrocardiography, transtoral echocardiography, daily Holter monitoring. The main attention was paid to the study of the parameters of the left ventricle. Students t-test was used to determine the significance of the differences, the results at p 0.05 were considered reliable. It was established that adolescents with hyperuricemia were more often diagnosed with primary and secondary arterial hypertension, less often with labile arterial hypertension and autonomic dysfunction syndrome by hypertensive type, and adolescents without hyperuricemia were equally often diagnosed with primary arterial hypertension and labile arterial hypertension, autonomic dysfunction syndrome by hypertensive type. Signs of left ventricular remodeling according to echocardiography were more often noted in boys without hyperuricemia (62.5% of cases) than in girls without hyperuricemia (10%; p 0.01) and in boys with hyperuricemia (26.7%; p 0,05). The findings indicated more significant changes in the morphofunctional state of the cardiovascular system in adolescents with hypertensive conditions and manifestations of metabolic syndrome without hyperuricemia, which requires further study.

scholarly journals A Preclinical Rat Model of Heart Failure With Preserved Ejection Fraction With Multiple Comorbidities

2022 ◽  
Vol 8 ◽  
Author(s):  
Géraldine Hubesch ◽  
Aliénor Hanthazi ◽  
Angela Acheampong ◽  
Laura Chomette ◽  
Hélène Lasolle ◽  
...  
Keyword(s):  
Heart Failure ◽  
Metabolic Syndrome ◽  
Ejection Fraction ◽  
Diastolic Dysfunction ◽  
High Fat Diet ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Sequencing Analysis ◽  
Preserved Ejection Fraction ◽  
High Fat

Heart failure with preserved ejection fraction (HFpEF) is a common complex clinical syndrome for which there are currently few evidence-based therapies. As patients with HFpEF very often present with comorbidities comprising the metabolic syndrome, we hypothesized, that metabolic syndrome could lead over time to the development of diastolic dysfunction and HFpEF. Obesity-prone rats were exposed to high-fat diet and compared to obesity-resistant rats fed with standard chow. Phenotyping of metabolic syndrome, associated with echocardiographic and cardiac hemodynamic measurements, was performed after 4 and 12 months. Blood and myocardial tissue sampling were performed for pathobiological evaluation. High-fat diet in obesity-prone rats elicited metabolic syndrome, characterized by increased body and abdominal fat weights, glucose intolerance and hyperlipidemia, as well as increased left ventricular (LV) systolic pressure (after 12 months). This was associated with LV diastolic dysfunction (assessed by increased LV end-diastolic pressure) and pulmonary hypertension (assessed by increased right ventricular systolic pressure). Echocardiography revealed significant concentric LV hypertrophy, while LV ejection fraction was preserved. LV remodeling was associated with cardiomyocyte hypertrophy, as well as myocardial and perivascular fibrosis. Circulating levels of soluble ST2 (the interleukin-1 receptor-like) markedly increased in rats with HFpEF, while plasma NT-proBNP levels decreased. RNA-sequencing analysis identified clusters of genes implicated in fatty acid metabolism and calcium-dependent contraction as upregulated pathways in the myocardium of rats with HFpEF. High-fat diet during 12 months in obesity-prone rats led to the development of a relevant preclinical model of HFpEF with multiple comorbidities, suitable for investigating novel therapeutic interventions.

Partial deletion of ROCK2 protects mice from high-fat diet-induced cardiac insulin resistance and contractile dysfunction

2015 ◽  
Vol 309 (1) ◽  
pp. H70-H81 ◽  
Author(s):  
Hesham Soliman ◽  
Vongai Nyamandi ◽  
Marysol Garcia-Patino ◽  
Julia Nogueira Varela ◽  
Girish Bankar ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cardiac Dysfunction ◽  
Performance Index ◽  
High Fat Diet ◽  
Left Ventricular ◽  
Myocardial Performance Index ◽  
Contractile Dysfunction ◽  
Myocardial Performance ◽  
High Fat ◽  
Glut4 Expression

Obesity is associated with cardiac insulin resistance and contractile dysfunction, which contribute to the development of heart failure. The RhoA-Rho kinase (ROCK) pathway has been reported to modulate insulin resistance, but whether it is implicated in obesity-induced cardiac dysfunction is not known. To test this, wild-type (WT) and ROCK2+/− mice were fed normal chow or a high-fat diet (HFD) for 17 wk. Whole body insulin resistance, determined by an insulin tolerance test, was observed in HFD-WT, but not HFD-ROCK2+/−, mice. The echocardiographically determined myocardial performance index, a measure of global systolic and diastolic function, was significantly increased in HFD-WT mice, indicating a deterioration of cardiac function. However, no change in myocardial performance index was found in hearts from HFD-ROCK2+/− mice. Speckle-tracking-based strain echocardiography also revealed regional impairment in left ventricular wall motion in hearts from HFD-WT, but not HFD-ROCK2+/−, mice. Activity of ROCK1 and ROCK2 was significantly increased in hearts from HFD-WT mice, and GLUT4 expression was significantly reduced. Insulin-induced phosphorylation of insulin receptor substrate (IRS) Tyr612, Akt, and AS160 was also impaired in these hearts, while Ser307 phosphorylation of IRS was increased. In contrast, the increase in ROCK2, but not ROCK1, activity was prevented in hearts from HFD-ROCK2+/− mice, and cardiac levels of TNFα were reduced. This was associated with normalization of IRS phosphorylation, downstream insulin signaling, and GLUT4 expression. These data suggest that increased activation of ROCK2 contributes to obesity-induced cardiac dysfunction and insulin resistance and that inhibition of ROCK2 may constitute a novel approach to treat this condition.

Targeted inhibition of activin receptor-like kinase 5 signaling attenuates cardiac dysfunction following myocardial infarction

2010 ◽  
Vol 298 (5) ◽  
pp. H1415-H1425 ◽  
Author(s):  
Sih Min Tan ◽  
Yuan Zhang ◽  
Kim A. Connelly ◽  
Richard E. Gilbert ◽  
Darren J. Kelly
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Dysfunction ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Type I ◽  
Artery Ligation ◽  
Receptor Like Kinase

Following myocardial infarction (MI), the heart undergoes a pathological process known as remodeling, which in many instances results in cardiac dysfunction and ultimately heart failure and death. Transforming growth factor-β (TGF-β) is a key mediator in the pathogenesis of cardiac remodeling following MI. We thus aimed to inhibit TGF-β signaling using a novel orally active TGF-β type I receptor [activin receptor-like kinase 5 (ALK5)] inhibitor (GW788388) to attenuate left ventricular remodeling and cardiac dysfunction in a rat model of MI. Sprague-Dawley rats underwent left anterior descending coronary artery ligation to induce experimental MI and then were randomized to receive GW788388 at a dosage of 50 mg·kg−1·day−1 or vehicle 1 wk after surgery. After 4 wk of treatment, echocardiography was performed before the rats were euthanized. Animals that received left anterior descending coronary artery ligation demonstrated systolic dysfunction, Smad2 activation, myofibroblasts accumulation, collagen deposition, and myocyte hypertrophy (all P < 0.05). Treatment with GW788388 significantly attenuated systolic dysfunction in the MI animals, together with the attenuation of the activated (phosphorylated) Smad2 ( P < 0.01), α-smooth muscle actin ( P < 0.001), and collagen I ( P < 0.05) in the noninfarct zone of MI rats. Cardiomyocyte hypertrophy in MI hearts was also attenuated by ALK5 inhibition ( P < 0.05). In brief, treatment with a novel TGF-β type I receptor inhibitor, GW788388, significantly reduced TGF-β activity, leading to the attenuation of systolic dysfunction and left ventricular remodeling in an experimental rat model of MI.

Left ventricular remodeling in patients with metabolic syndrome: Influence of gender

2013 ◽  
Vol 23 (8) ◽  
pp. 771-775 ◽  
Author(s):  
E. Nicolini ◽  
G. Martegani ◽  
A.M. Maresca ◽  
C. Marchesi ◽  
F. Dentali ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular
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