The role of calcium handling in the improved contractile function associated with high‐fat feeding in heart failure

Previous studies have reported that high fat feeding in mild to moderate heart failure (HF) results in the preservation of contractile function. Recent evidence has suggested that preventing the switch from fatty acid to glucose metabolism in HF may ameliorate dysfunction, and insulin resistance is one potential mechanism for regulating substrate utilization. This study was designed to determine whether peripheral and myocardial insulin resistance exists with HF and/or a high-fat diet and whether myocardial insulin signaling was altered accordingly. Rats underwent coronary artery ligation (HF) or sham surgery and were randomized to normal chow (NC; 14% kcal from fat) or a high-fat diet (SAT; 60% kcal from fat) for 8 wk. HF + SAT animals showed preserved systolic (+dP/d t and stroke work) and diastolic (−dP/d t and time constant of relaxation) function compared with HF + NC animals. Glucose tolerance tests revealed peripheral insulin resistance in sham + SAT, HF + NC, and HF + SAT animals compared with sham + NC animals. PET imaging confirmed myocardial insulin resistance only in HF + SAT animals, with an uptake ratio of 2.3 ± 0.3 versus 4.6 ± 0.7, 4.3 ± 0.4, and 4.2 ± 0.6 in sham + NC, sham + SAT, and HF + NC animals, respectively; the myocardial glucose utilization rate was similarly decreased in HF + SAT animals only. Western blot analysis of insulin signaling protein expression was indicative of cardiac insulin resistance in HF + SAT animals. Specifically, alterations in Akt and glycogen synthase kinase-3β protein expression in HF + SAT animals compared with HF + NC animals may be involved in mediating myocardial insulin resistance. In conclusion, HF animals fed a high-saturated fat exhibited preserved myocardial contractile function, peripheral and myocardial insulin resistance, decreased myocardial glucose utilization rates, and alterations in cardiac insulin signaling. These results suggest that myocardial insulin resistance may serve a cardioprotective function with high fat feeding in mild to moderate HF.

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Abstract 88: A Crucial Role of BAG3 in Preventing Dilated Cardiomyopathy

Circulation Research ◽

10.1161/res.121.suppl_1.88 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Xi Fang ◽

Julius Bogomolovas ◽

Wei Zhang ◽

Tongbin Wu ◽

Canzhao Liu ◽

...

Keyword(s):

Heart Failure ◽

Dilated Cardiomyopathy ◽

Protein Quality ◽

Contractile Function ◽

Metabolic Stress ◽

Insoluble Fraction ◽

Therapeutic Benefit ◽

Loss Of Function ◽

Specific Subset

Defective protein quality control (PQC) systems are implicated in multiple diseases, with molecular chaperones/co-chaperones being critical to PQC. Cardiomyocytes are constantly challenged by mechanical and metabolic stress, placing great demand on the PQC system. Mutations and downregulation of the co-chaperone protein B cl-2- a ssociated athano g ene 3 (BAG3) are associated with cardiac myopathy and heart failure, and a BAG3 E455K mutation leads to Dilated cardiomyopathy (DCM). However, the role of BAG3 in the heart and mechanisms by which the E455K mutation lead to DCM remained obscure. Here, we found that cardiac-specific BAG3 knockout (CKO) and cardiac-specific E455K BAG3 knockin mice developed DCM. Comparable phenotypes in the two mutants demonstrated that the E455K mutation resulted in loss-of-function, and experiments revealed that the E455K mutation disrupted interaction between BAG3 and HSP70. In both mutants, decreased levels of small heat shock proteins (sHSPs) were observed, and a specific subset of proteins required for metabolic and contractile function of cardiomyocytes was enriched in the insoluble fraction. Together, these observations suggested that interaction between BAG3 and HSP70 was essential for BAG3 to stabilize sHSPs and maintain cardiomyocyte protein homeostasis. Our results provide new insight into the pathogenesis of heart failure caused by defects in BAG3 pathways, suggesting that increasing protein levels of BAG3 may be of therapeutic benefit in heart failure.

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Modeling heart failure risk in diabetes and kidney disease: limitations and potential applications of transverse aortic constriction in high-fat-fed mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00357.2017 ◽

2018 ◽

Vol 314 (6) ◽

pp. R858-R869 ◽

Cited By ~ 4

Author(s):

Wei Sheng Tan ◽

Thomas P. Mullins ◽

Melanie Flint ◽

Sarah L. Walton ◽

Helle Bielefeldt-Ohmann ◽

...

Keyword(s):

Heart Failure ◽

Kidney Disease ◽

Left Ventricular ◽

Cardiomyocyte Hypertrophy ◽

Transverse Aortic Constriction ◽

High Fat ◽

Aortic Constriction ◽

Failure Risk ◽

Cardiovascular Prognosis ◽

Fat Feeding

There is an increased incidence of heart failure in individuals with diabetes mellitus (DM). The coexistence of kidney disease in DM exacerbates the cardiovascular prognosis. Researchers have attempted to combine the critical features of heart failure, using transverse aortic constriction, with DM in mice, but variable findings have been reported. Furthermore, kidney outcomes have not been assessed in this setting; thus its utility as a model of heart failure in DM and kidney disease is unknown. We generated a mouse model of obesity, hyperglycemia, and mild kidney pathology by feeding male C57BL/6J mice a high-fat diet (HFD). Cardiac pressure overload was surgically induced using transverse aortic constriction (TAC). Normal diet (ND) and sham controls were included. Heart failure risk factors were evident at 8-wk post-TAC, including increased left ventricular mass (+49% in ND and +35% in HFD), cardiomyocyte hypertrophy (+40% in ND and +28% in HFD), and interstitial and perivascular fibrosis (Masson’s trichrome and picrosirius red positivity). High-fat feeding did not exacerbate the TAC-induced cardiac outcomes. At 11 wk post-TAC in a separate mouse cohort, echocardiography revealed reduced left ventricular size and increased left ventricular wall thickness, the latter being evident in ND mice only. Systolic function was preserved in the TAC mice and was similar between ND and HFD. Thus combined high-fat feeding and TAC in mice did not model the increased incidence of heart failure in DM patients. This model, however, may mimic the better cardiovascular prognosis seen in overweight and obese heart failure patients.

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The role of action potential prolongation and altered intracellular calcium handling in the pathogenesis of heart failure

Cardiovascular Research ◽

10.1016/s0008-6363(97)00256-3 ◽

1998 ◽

Vol 37 (2) ◽

pp. 312-323 ◽

Cited By ~ 104

Author(s):

A Wickenden

Keyword(s):

Heart Failure ◽

Action Potential ◽

Intracellular Calcium ◽

Calcium Handling ◽

Action Potential Prolongation

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Differential effects of high-fat diet on myocardial lipid metabolism in failing and nonfailing hearts with angiotensin II-mediated cardiac remodeling in mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01023.2011 ◽

2012 ◽

Vol 302 (9) ◽

pp. H1795-H1805 ◽

Cited By ~ 9

Author(s):

Corinne Pellieux ◽

Christophe Montessuit ◽

Irène Papageorgiou ◽

Thierry Pedrazzini ◽

René Lerch

Keyword(s):

Heart Failure ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

High Fat Diet ◽

Regulatory Proteins ◽

Acid Oxidation ◽

Contractile Dysfunction ◽

High Fat ◽

Palmitate Oxidation ◽

Fat Feeding

Normal myocardium adapts to increase of nutritional fatty acid supply by upregulation of regulatory proteins of the fatty acid oxidation pathway. Because advanced heart failure is associated with reduction of regulatory proteins of fatty acid oxidation, we hypothesized that failing myocardium may not be able to adapt to increased fatty acid intake and therefore undergo lipid accumulation, potentially aggravating myocardial dysfunction. We determined the effect of high-fat diet in transgenic mice with overexpression of angiotensinogen in the myocardium (TG1306/R1). TG1306/R1 mice develop ANG II-mediated left ventricular hypertrophy, and at one year of age approximately half of the mice present heart failure associated with reduced expression of regulatory proteins of fatty acid oxidation and reduced palmitate oxidation during ex vivo working heart perfusion. Hypertrophied hearts from TG1306/R1 mice without heart failure adapted to high-fat feeding, similarly to hearts from wild-type mice, with upregulation of regulatory proteins of fatty acid oxidation and enhancement of palmitate oxidation. There was no myocardial lipid accumulation or contractile dysfunction. In contrast, hearts from TG1306/R1 mice presenting heart failure were unable to respond to high-fat feeding by upregulation of fatty acid oxidation proteins and enhancement of palmitate oxidation. This resulted in accumulation of triglycerides and ceramide in the myocardium, and aggravation of contractile dysfunction. In conclusion, hearts with ANG II-induced contractile failure have lost the ability to enhance fatty acid oxidation in response to increased fatty acid supply. The ensuing accumulation of lipid compounds may play a role in the observed aggravation of contractile dysfunction.

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Impact of Atrial Fibrillation on Ventricular Calcium Handling and Contractile Function: The Role of Irregularity

Heart Lung and Circulation ◽

10.1016/j.hlc.2010.06.875 ◽

2010 ◽

Vol 19 ◽

pp. S89

Author(s):

L. Ling ◽

F. Amirahmadi ◽

A. Foster ◽

O. Khammy ◽

L. Stevenson ◽

...

Keyword(s):

Atrial Fibrillation ◽

Contractile Function ◽

Calcium Handling

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Phosphorylation of cardiac myosin–binding protein-C contributes to calcium homeostasis

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.013296 ◽

2020 ◽

Vol 295 (32) ◽

pp. 11275-11291 ◽

Cited By ~ 1

Author(s):

Mohit Kumar ◽

Kobra Haghighi ◽

Evangelia G. Kranias ◽

Sakthivel Sadayappan

Keyword(s):

Heart Failure ◽

Protein C ◽

Contractile Function ◽

Binding Protein ◽

Stress Conditions ◽

Calcium Handling ◽

Cardiac Myosin ◽

Myosin Binding Protein ◽

Myosin Binding Protein C ◽

Myosin Binding

Cardiac myosin–binding protein-C (cMyBP-C) is highly phosphorylated under basal conditions. However, its phosphorylation level is decreased in individuals with heart failure. The necessity of cMyBP-C phosphorylation for proper contractile function is well-established, but the physiological and pathological consequences of decreased cMyBP-C phosphorylation in the heart are not clear. Herein, using intact adult cardiomyocytes from mouse models expressing phospho-ablated (AAA) and phosphomimetic (DDD) cMyBP-C as well as controls, we found that cMyBP-C dephosphorylation is sufficient to reduce contractile parameters and calcium kinetics associated with prolonged decay time of the calcium transient and increased diastolic calcium levels. Isoproterenol stimulation reversed the depressive contractile and Ca2+-kinetic parameters. Moreover, caffeine-induced calcium release yielded no difference between AAA/DDD and controls in calcium content of the sarcoplasmic reticulum. On the other hand, sodium–calcium exchanger function and phosphorylation levels of calcium-handling proteins were significantly decreased in AAA hearts compared with controls. Stress conditions caused increases in both spontaneous aftercontractions in AAA cardiomyocytes and the incidence of arrhythmias in vivo compared with the controls. Treatment with omecamtiv mecarbil, a positive cardiac inotropic drug, rescued the contractile deficit in AAA cardiomyocytes, but not the calcium-handling abnormalities. These findings indicate a cascade effect whereby cMyBP-C dephosphorylation causes contractile defects, which then lead to calcium-cycling abnormalities, resulting in aftercontractions and increased incidence of cardiac arrhythmias under stress conditions. We conclude that improvement of contractile deficits alone without improving calcium handling may be insufficient for effective management of heart failure.

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Mechanisms Underlying Development of Taurine-Deficient Cardiomyopathy

Hearts ◽

10.3390/hearts1020010 ◽

2020 ◽

Vol 1 (2) ◽

pp. 86-98

Author(s):

Stephen Schaffer ◽

Takashi Ito ◽

Junichi Azuma ◽

Chian Jong ◽

Jay Kramer

Keyword(s):

Heart Failure ◽

Congestive Heart Failure ◽

Respiratory Chain ◽

Complex I ◽

Myocardial Function ◽

Calcium Handling ◽

A Subunit ◽

Atp Generation ◽

Taurine Conjugate

Taurine is a ubiquitous β-amino acid that plays an essential role in ensuring normal mitochondrial and myocardial function. In the mitochondria, taurine reacts with a tRNA forming a 5-taurinomethyluridine conjugate that primarily regulates the biosynthesis of the mitochondria encoded protein, ND6, which serves as a subunit of complex I of the respiratory chain. Impaired formation of the taurine conjugate reduces activity of complex I and plays a central role in the pathophysiology of the mitochondrial disease MELAS (myopathy, encephalopathy, lactic acidosis and stroke-like episodes). The restoration of mitochondrial levels of the taurine conjugate enhances electron flux through the respiratory chain, thereby preventing at least some of the symptoms of MELAS. Taurine therapy also diminishes the severity of congestive heart failure, an observation that led to its approval for the treatment of congestive heart failure in Japan. The review article discusses the role of defective calcium handling, reduced ATP generation, enhanced oxidative stress and apoptosis in the development of taurine-deficient cardiomyopathy. Some patients suffering from congestive heart failure are taurine-deficient, an observation supporting the hypothesis that low taurine levels contribute to the severity of heart failure. Thus, mishandling of taurine leads to mitochondrial dysfunction, which is involved in the development of both MELAS and congestive heart failure.

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