Seipin Knockout Mice Develop Heart Failure With Preserved Ejection Fraction

Bai, Bo; Yang, Wulin; Fu, Yangyang; Foon, Hannah Lee; Tay, Wan Ting; Yang, Keli; Luo, Cuiting; Gunaratne, Jayantha; Lee, Philip; Zile, Michael R.; Xu, Aiguo; Chin, Calvin Woon-Loong; Lam, Carolyn S.P.; Han, Weiping; Wang, Yu

doi:10.1016/j.jacbts.2019.07.008

Cited by 35 publications

(39 citation statements)

References 56 publications

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“…NET was characterized by intact neutrophils with condensed nuclei (15 weeks old) and persisted as large amorphous extracellular structures, released DNA fibers decorated with MPO, and citrullinated histone (32 weeks old). By the age of 24 weeks, the mRNA and protein levels of the markers of cardiac inflammation and fibrosis, such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF- α ), intercellular adhesion molecule-1, collagen 1, alpha-smooth muscle actin, and transforming growth factor beta family, were significantly increased in the heart of seipin/Bslc2 knockout mice [ 53 ]. In heart tissue of seipin/Bslc2 knockout mice, hyperphosphorylation of JAK2 and downstream STAT3 was also found [ 53 ], suggesting that JAK2 signal can be connected to myocardial dysfunction and NETosis.…”

Section: Netosis Phenomena In Hfmentioning

confidence: 99%

NETosis as a Pathogenic Factor for Heart Failure

Ling

2021

Oxidative Medicine and Cellular Longevity

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Heart failure threatens the lives of patients and reduces their quality of life. Heart failure, especially heart failure with preserved ejection fraction, is closely related to systemic and local cardiac persistent chronic low-grade aseptic inflammation, microvascular damage characterized by endothelial dysfunction, oxidative stress, myocardial remodeling, and fibrosis. However, the initiation and development of persistent chronic low-grade aseptic inflammation is unexplored. Oxidative stress-mediated neutrophil extracellular traps (NETs) are the main immune defense mechanism against external bacterial infections. Furthermore, NETs play important roles in noninfectious diseases. After the onset of myocardial infarction, atrial fibrillation, or myocarditis, neutrophils infiltrate the damaged tissue and aggravate inflammation. In tissue injury, damage-related molecular patterns (DAMPs) may induce pattern recognition receptors (PRRs) to cause NETs, but whether NETs are directly involved in the pathogenesis and development of heart failure and the mechanism is still unclear. In this review, we analyzed the markers of heart failure and heart failure-related diseases and comorbidities, such as mitochondrial DNA, high mobility box group box 1, fibronectin extra domain A, and galectin-3, to explore their role in inducing NETs and to investigate the mechanism of PRRs, such as Toll-like receptors, receptor for advanced glycation end products, cGAS-STING, and C-X-C motif chemokine receptor 2, in activating NETosis. Furthermore, we discussed oxidative stress, especially the possibility that imbalance of thiol redox and MPO-derived HOCl promotes the production of 2-chlorofatty acid and induces NETosis, and analyzed the possibility of NETs triggering coronary microvascular thrombosis. In some heart diseases, the deletion or blocking of neutrophil-specific myeloperoxidase and peptidylarginine deiminase 4 has shown effectiveness. According to the results of current pharmacological studies, MPO and PAD4 inhibitors are effective at least for myocardial infarction, atherosclerosis, and certain autoimmune diseases, whose deterioration can lead to heart failure. This is essential for understanding NETosis as a therapeutic factor of heart failure and the related new pathophysiology and therapeutics of heart failure.

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Section: Netosis Phenomena In Hfmentioning

confidence: 99%

NETosis as a Pathogenic Factor for Heart Failure

Ling

2021

Oxidative Medicine and Cellular Longevity

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“…Overall, the Bslc2 –/– mouse displayed features of diastolic dysfunction and failure and recapitulated several characteristics of the lean diabetic patient with HFpEF (5). However, it is noteworthy that the glycemic levels of the Bslc2 –/– mice were extremely high (>20 mM or >360 mg/dl) in the absence of any type of glycemic control, which is expected to be better managed in patients undergoing clinical assessment, treatment, and follow-up.…”

mentioning

confidence: 69%

“…Intriguingly, all the reported changes were independent from direct effects due to the BSLC2 deletion in cardiomyocytes (5). In fact, Bscl2 messenger ribonucleic acid was barely expressed in the muscle tissue and in the heart of Bslc2 +/+ mice, whereas it was mostly expressed in the white and brown adipose tissues.…”

mentioning

confidence: 89%

“…Recent epidemiological studies have shown that patients with HFpEF and diabetes in Asia are more likely to be lean compared with North European white patients with diabetes and HFpEF, who are prevalently obese (4,5). This patient population seems different from other patients usually seen in the clinics in the Western countries.…”

mentioning

confidence: 99%

“…The study by Bai et al. (5) in this issue of JACC: Basic to Translational Science explored the effect of Bslc2 (seipin) deletion in mice to reproduce the diabetic lean phenotype while aiming to recapitulate some of the characteristics of the Asian diabetic patient population with HFpEF. The Berardinelli-Seip congenital lipodystrophy-2 ( Bslc2) /seipin mutation in human patients induces a lipodystrophic phenotype (leanness, diabetes) with left ventricular hypertrophy and normal ejection fraction.…”

mentioning

confidence: 99%

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The Bslc2–/– Mouse

Salloum

Toldo

2019

JACC: Basic to Translational Science

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BSCL2/Seipin deficiency in hearts causes cardiac energy deficit and dysfunction via inducing excessive lipid catabolism

Zhou

et al. 2022

Clinical & Translational Med

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Background Heart failure (HF) is one of the leading causes of death worldwide 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 with reduced cardiac steatosis. Whether BSCL2 plays a direct role in regulating cardiac substrate metabolism and/or contractile function remains unknown. Methods We generated mice with cardiomyocyte‐specific deletion of Bscl2 ( Bscl2 cKO ) and studied their cardiac substrate utilisation, bioenergetics, lipidomics and contractile function under baseline or after either a treatment regimen using fatty acid oxidation (FAO) inhibitor trimetazidine (TMZ) or a prevention regimen with high‐fat diet (HFD) feeding. Mice with partial ATGL deletion and cardiac‐specific deletion of Bscl2 were also generated followed by cardiac phenotyping. Results Different from hypertrophic cardiomyopathy in Bscl2 −/− mice, mice with cardiac‐specific deletion of Bscl2 developed systolic dysfunction with dilation. Myocardial BSCL2 deletion led to elevated ATGL expression and 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, cardiac dysfunction in Bscl2 cKO mice could be partially reversed by FAO inhibitor TMZ, or prevented by genetic abolishment of one ATGL allele or HFD feeding. Lipidomic analysis further identified markedly reduced glycerolipids, glycerophospholipids, NEFA and acylcarnitines in Bscl2 cKO hearts, which were partially normalised by TMZ or HFD. Conclusions We identified a new form of cardiac dysfunction with excessive lipid utilisation which ultimately causes cardiac substrate depletion and bioenergetics failure. Our findings also uncover a crucial role of BSCL2 in controlling cardiac lipid catabolism and contractile function and provide novel insights into metabolically treating energy‐starved HF using FAO inhibitor or HFD.

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Seipin Knockout Mice Develop Heart Failure With Preserved Ejection Fraction

Abstract: Visual Abstract

Cited by 35 publications

References 56 publications

NETosis as a Pathogenic Factor for Heart Failure

NETosis as a Pathogenic Factor for Heart Failure

The Bslc2–/– Mouse

BSCL2/Seipin deficiency in hearts causes cardiac energy deficit and dysfunction via inducing excessive lipid catabolism

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