Abstract P462: Bscl2/seipin Deficiency In Heart Causes Energy Deficit And Heart Failure Via Inducing Excessive Lipid Catabolism

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Hongyi Zhou ◽  
Jie Li ◽  
Huabo Su ◽  
Ji Li ◽  
Todd A Lydic ◽  
...  
Keyword(s):  
Heart Failure ◽  
Contractile Function ◽  
Energy State ◽  
Energy Deficit ◽  
Direct Role ◽  
Cardiac Lipid ◽  
Lipid Catabolism ◽  
Metabolic Reserve

Heart failure (HF) is one of the leading causes of death world-wide and is associated with cardiac metabolic perturbations. Human Type 2 Berardinelli-Seip Congenital Lipodystrophy (BSCL2) disease is caused by mutations in the BSCL2 gene. Global lipodystrophic Bscl2 –/– mice exhibit hypertrophic cardiomyopathy. Whether BSCL2 plays a direct role in regulating cardiac substrate metabolism and/or contractile function remains unknown. Here we show that mice with cardiac-specific deletion of Bscl2 ( Bscl2 cKO ) developed dilated HF. Myocardial BSCL2 deletion led to elevated ATGL expression and FA oxidation (FAO) along with reduced cardiac lipid contents. Cardiac dysfunction in Bscl2 cKO mice was independent of mitochondrial dysfunction and oxidative stress, but associated with decreased metabolic reserve and ATP levels. Importantly, heart failure in Bscl2 cKO mice could be partially reversed by pharmacological inhibition of FAO, or prevented by high fat diet (HFD) feeding. Lipidomic analysis further identified markedly reduced glycerolipids, glycerophospholipids, NEFA and acylcarnitines in Bscl2 cKO hearts, which were partially normalized by FAO inhibition or HFD. Our study reveals a new form of HF with excessive lipid catabolism, and identifies a crucial cardiomyocyte-specific role of BSCL2 in controlling cardiac lipid catabolism, energy state and contractile function. It also provides novel insights into metabolically treating energy-starved HF using FAO inhibitor or HFD.

scholarly journals BSCL2/Seipin Deficiency in Heart Causes Energy Deficit and Heart Failure via Inducing Excessive Lipid Catabolism

2021 ◽  
Author(s):  
Hongyi Zhou ◽  
Jie Li ◽  
Huabo Su ◽  
Ji Li ◽  
Todd A Lydic ◽  
...  
Keyword(s):  
Heart Failure ◽  
Contractile Function ◽  
Energy State ◽  
Energy Deficit ◽  
Direct Role ◽  
Cardiac Lipid ◽  
Lipid Catabolism ◽  
Metabolic Reserve

Heart failure (HF) is one of the leading causes of death world-wide and is associated with cardiac metabolic perturbations. Human Type 2 Berardinelli-Seip Congenital Lipodystrophy (BSCL2) disease is caused by mutations in the BSCL2 gene. Global lipodystrophic Bscl2−/− mice exhibit hypertrophic cardiomyopathy. Whether BSCL2 plays a direct role in regulating cardiac substrate metabolism and/or contractile function remains unknown. Here we show that mice with cardiac-specific deletion of Bscl2 (Bscl2cKO) developed dilated HF. Myocardial BSCL2 deletion led to elevated ATGL expression and FA oxidation (FAO) along with reduced cardiac lipid contents. Cardiac dysfunction in Bscl2cKO mice was independent of mitochondrial dysfunction and oxidative stress, but associated with decreased metabolic reserve and ATP levels. Importantly, heart failure in Bscl2cKO mice could be partially reversed by pharmacological inhibition of FAO, or prevented by high fat diet (HFD) feeding. Lipidomic analysis further identified markedly reduced glycerolipids, glycerophospholipids, NEFA and acylcarnitines in Bscl2cKO hearts, which were partially normalized by FAO inhibition or HFD. Our study reveals a new form of HF with excessive lipid catabolism, and identifies a crucial cardiomyocyte-specific role of BSCL2 in controlling cardiac lipid catabolism, energy state and contractile function. It also provides novel insights into metabolically treating energy-starved HF using FAO inhibitor or HFD.

scholarly journals Towards a Consensus on Alzheimer’s Disease Comorbidity?

2021 ◽  
Vol 10 (19) ◽  
pp. 4360
Author(s):  
Iska Avitan ◽  
Yudit Halperin ◽  
Trishna Saha ◽  
Naamah Bloch ◽  
Dana Atrahimovich ◽  
...  
Keyword(s):  
Risk Factors ◽  
Heart Failure ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Potential Role ◽  
Oxygen Species ◽  
Degenerative Diseases ◽  
Comorbid Diseases

Alzheimer’s disease (AD) is often comorbid with other pathologies. First, we review shortly the diseases most associated with AD in the clinic. Then we query PubMed citations for the co-occurrence of AD with other diseases, using a list of 400 common pathologies. Significantly, AD is found to be associated with schizophrenia and psychosis, sleep insomnia and apnea, type 2 diabetes, atherosclerosis, hypertension, cardiovascular diseases, obesity, fibrillation, osteoporosis, arthritis, glaucoma, metabolic syndrome, pain, herpes, HIV, alcoholism, heart failure, migraine, pneumonia, dyslipidemia, COPD and asthma, hearing loss, and tobacco smoking. Trivially, AD is also found to be associated with several neurodegenerative diseases, which are disregarded. Notably, our predicted results are consistent with the previously published clinical data and correlate nicely with individual publications. Our results emphasize risk factors and promulgate diseases often associated with AD. Interestingly, the comorbid diseases are often degenerative diseases exacerbated by reactive oxygen species, thus underlining the potential role of antioxidants in the treatment of AD and comorbid diseases.

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

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.

New insights into the pathological role of TNF-α in early cardiac dysfunction and subsequent heart failure after infarction in rats

2004 ◽  
Vol 287 (1) ◽  
pp. H340-H350 ◽  
Author(s):  
C. Berthonneche ◽  
T. Sulpice ◽  
F. Boucher ◽  
L. Gouraud ◽  
J. de Leiris ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Diastolic Pressure ◽  
Subsequent Development ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Direct Role ◽  
Volume Curve ◽  
Tnf Α

A marked increase in plasma TNF-α has been described in patients with chronic heart failure (CHF). Nevertheless, little is known about the direct role of this cytokine early after myocardial infarction (MI) and its possible effects on the subsequent development of CHF. Wistar rats were subjected to permanent in vivo coronary artery ligation. At 5, 7, and 9 days after MI, cardiac function, passive compliance of the left ventricle (LV), and cardiac geometry were evaluated. The same model was used to perform pharmacological studies 7 days and 10 wk after MI in rats treated with monomeric recombinant human soluble TNF-α receptor type II (sTNF-RII, 40 μg/kg iv) or a placebo on day 3. Maximal alterations of cardiac function and geometry occurred 7 days after MI, which correlated chronologically with a peak of cardiac and serum TNF-α, as shown by immunohistochemistry and ELISA, respectively. sTNF-RII improved LV end-diastolic pressure under basal conditions and after volume overload 7 days and 10 wk after MI. Moreover, a significant leftward shift of the pressure-volume curve in the sTNF-RII-treated group 7 days after MI indicated a preservation of LV volume. Infarct expansion index was also significantly improved by sTNF-RII 7 days after MI ( P < 0.01). Nevertheless, 10 wk after MI, geometric indexes and passive pressure-volume curves were not significantly improved by the treatment. In conclusion, TNF-α plays a major role in cardiac alterations 7 days after MI in rats and contributes to hemodynamic derangement, but not to cardiac remodeling, in subsequent CHF.

scholarly journals Managing Common Co-morbidities in Heart Failure

2020 ◽  
Vol 15 (SP1) ◽  
pp. 14-21
Author(s):  
Phyllis Sin ◽  
Rohan Sanjanwala ◽  
Shelley Zieroth
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Clinical Trial Data ◽  
Heart Failure Patients ◽  
Iron Deficient ◽  
Risk Patients ◽  
The Impact

Heart failure increases in prevalence with age and is usually associated with various cardiac and non-cardiac comorbidities.  For common coexisting conditions such as renal dysfunction, anemia and type 2 diabetes mellitus, important pathophysiologic links have been implicated between cardiac dysfunction and the underlying condition.  Indeed, the number and severity of comorbidities in the setting of heart failure is an important driver of prognosis.  By targeting the management of coexisting diseases, it may be possible to improve functional capacity, quality of life and perhaps even overall mortality in heart failure patients.  Recent clinical trial data has provided insights into cardio-renal interactions in acute heart failure, the impact of iron replacement therapy in iron deficient heart failure patients, and the role of pharmacologic therapies to prevent heart failure related events in high risk patients with type 2 diabetes. 

scholarly journals Response to ‘The possible role of insulin and glucagon in patients with heart failure and Type 2 diabetes’

2019 ◽  
Vol 41 (2) ◽  
pp. 326-327
Author(s):  
Edoardo Bertero ◽  
Vasco Sequeira ◽  
Stephane Heymans ◽  
Christoph Maack
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Patients With Heart Failure

scholarly journals Comorbidity status of deceased COVID-19 in-patients in Italy

2021 ◽  
Author(s):  
Davide Liborio Vetrano ◽  
Clare Tazzeo ◽  
Luigi Palmieri ◽  
Alessandra Marengoni ◽  
Alberto Zucchelli ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Older Persons ◽  
Logistic Regression Models ◽  
Neuropsychiatric Diseases ◽  
Clinical Profiles ◽  
Comorbidity Status ◽  
Diabetes And Obesity

Abstract Background Most COVID-19-related deaths have occurred in older persons with comorbidities. Specific patterns of comorbidities related to COVID-19 deaths have not been investigated. Methods A random sample of 6085 individuals in Italy who died in-hospital with confirmed COVID-19 between February and December 2020 were included. Observed to expected (O/E) ratios of disease pairs were computed and logistic regression models were used to determine the association between disease pairs with O/E values ≥ 1.5. Results Six pairs of diseases exhibited O/E values ≥ 1.5 and statistically significant higher odds of co-occurrence in the crude and adjusted analyses: (1) ischemic heart disease and atrial fibrillation, (2) atrial fibrillation and heart failure, (3) atrial fibrillation and stroke, (4) heart failure and COPD, (5) stroke and dementia, and (6) type 2 diabetes and obesity. Conclusion In those deceased in-hospital due to COVID-19 in Italy, disease combinations defined by multiple cardio-respiratory, metabolic, and neuropsychiatric diseases occur more frequently than expected. This finding indicates a need to investigate the possible role of these clinical profiles in the chain of events that lead to death in individuals who have contracted SARS-CoV-2.

scholarly journals Bscl2 Deficiency Does Not Directly Impair the Innate Immune Response in a Murine Model of Generalized Lipodystrophy

2021 ◽  
Vol 10 (3) ◽  
pp. 441
Author(s):  
Ahlima Roumane ◽  
George D. Mcilroy ◽  
Arda Balci ◽  
Weiping Han ◽  
Mirela Delibegović ◽  
...  
Keyword(s):  
Metabolic Disease ◽  
Immune Response ◽  
Innate Immune Response ◽  
Severe Form ◽  
Innate Immune ◽  
Direct Role ◽  
Myeloid Lineage ◽  
Susceptibility To Infection

Congenital Generalized Lipodystrophy type 2 (CGL2) is the most severe form of lipodystrophy and is caused by mutations in the BSCL2 gene. Affected patients exhibit a near complete lack of adipose tissue and suffer severe metabolic disease. A recent study identified infection as a major cause of death in CGL2 patients, leading us to examine whether Bscl2 loss could directly affect the innate immune response. We generated a novel mouse model selectively lacking Bscl2 in the myeloid lineage (LysM-B2KO) and also examined the function of bone-marrow-derived macrophages (BMDM) isolated from global Bscl2 knockout (SKO) mice. LysM-B2KO mice failed to develop lipodystrophy and metabolic disease, providing a model to study the direct role of Bscl2 in myeloid lineage cells. Lipopolysaccharide-mediated stimulation of inflammatory cytokines was not impaired in LysM-B2KO mice or in BMDM isolated from either LysM-B2KO or SKO mice. Additionally, intracellular fate and clearance of bacteria in SKO BMDM challenged with Staphylococcus aureus was indistinguishable from that in BMDM isolated from littermate controls. Overall, our findings reveal that selective Bscl2 deficiency in macrophages does not critically impact the innate immune response to infection. Instead, an increased susceptibility to infection in CGL2 patients is likely to result from severe metabolic disease.

Sign in / Sign up

Export Citation Format

Share Document