A potential role of caspase recruitment domain family member 9 (Card9) in transverse aortic constriction-induced cardiac dysfunction, fibrosis, and hypertrophy

2020 ◽  
Vol 43 (12) ◽  
pp. 1375-1384 ◽  
Author(s):  
Matthew R. Peterson ◽  
Yohannes Getiye ◽  
Luiza Bosch ◽  
Alyssa J. Sanders ◽  
Aspen R. Smith ◽  
...  
Keyword(s):  
Family Member ◽  
Cardiac Dysfunction ◽  
Potential Role ◽  
Transverse Aortic Constriction ◽  
Domain Family ◽  
Aortic Constriction ◽  
Caspase Recruitment Domain

scholarly journals A disintegrin and metalloproteinase 12 prevents heart failure by regulating cardiac hypertrophy and fibrosis

2020 ◽  
Vol 318 (2) ◽  
pp. H238-H251 ◽  
Author(s):  
Yuto Nakamura ◽  
Shunbun Kita ◽  
Yoshimitsu Tanaka ◽  
Shiro Fukuda ◽  
Yoshinari Obata ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Focal Adhesion ◽  
Cardiac Dysfunction ◽  
Transverse Aortic Constriction ◽  
Wild Type ◽  
Aortic Constriction ◽  
A Disintegrin And Metalloproteinase ◽  
Adam 12

A disintegrin and metalloproteinase (ADAM)12 is considered to promote cardiac dysfunction based on the finding that a small-molecule ADAM12 inhibitor, KB-R7785, ameliorated cardiac function in a transverse aortic constriction (TAC) model by inhibiting the proteolytic activation of heparin-binding-EGF signaling. However, this compound has poor selectivity for ADAM12, and the role of ADAM12 in cardiac dysfunction has not yet been investigated using genetic loss-of-function mice. We revealed that ADAM12 knockout mice showed significantly more advanced cardiac hypertrophy and higher mortality rates than wild-type mice 4 wk after TAC surgery. An ADAM12 deficiency resulted in significantly more expanded cardiac fibrosis accompanied by increased collagen-related gene expression in failing hearts. The results of a genome-wide transcriptional analysis suggested a strongly enhanced focal adhesion- and fibrosis-related signaling pathway in ADAM12 knockout hearts. The loss of ADAM12 increased the abundance of the integrinβ1 subunit and transforming growth factor (TGF)-β receptor types I and III, and this was followed by the phosphorylation of focal adhesion kinase, Akt, mammalian target of rapamycin, ERK, and Smad2/3 in the heart, which resulted in cardiac dysfunction. The present results revealed that the loss of ADAM12 enhanced focal adhesion and canonical TGF-β signaling by regulating the abundance of the integrinβ1 and TGF-β receptors. NEW & NOTEWORTHY In contrast to a long-believed cardio-damaging role of a disintegrin and metalloproteinase (ADAM)12, cardiac hypertrophy was more severe, cardiac function was lower, and mortality was higher in ADAM12 knockout mice than in wild-type mice after transverse aortic constriction surgery. The loss of ADAM12 enhanced focal adhesion- and fibrosis-related signaling pathways in the heart, which may compromise cardiac function. These results provide insights for the development of novel therapeutics that target ADAM12 to treat heart failure.

scholarly journals Aerobic Exercise Attenuates Pressure Overload-Induced Cardiac Dysfunction through Promoting Skeletal Muscle Microcirculation and Increasing Muscle Mass

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Ling-Yan Yuan ◽  
Pei-Zhao Du ◽  
Min-Min Wei ◽  
Qi Zhang ◽  
Le Lu ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cardiac Function ◽  
Aerobic Exercise ◽  
Muscle Mass ◽  
Cardiac Dysfunction ◽  
Pressure Overload ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Protein Levels ◽  
Skeletal Muscle Microcirculation

Background. Aerobic exercise has been proven to have a positive effect on cardiac function after hypertension; however, the mechanism is not entirely clarified. Skeletal muscle mass and microcirculation are closely associated with blood pressure and cardiac function. Objective. This study was designed to investigate the effects of aerobic exercise on the skeletal muscle capillary and muscle mass, to explore the possible mechanisms involved in exercise-induced mitigation of cardiac dysfunction in pressure overload mice. Methods. In this study, 60 BALB/C mice aged 8 weeks were randomly divided into 3 groups: control (CON), TAC, and TAC plus exercise (TAE) group and utilized transverse aortic constriction (TAC) to establish hypertensive model; meanwhile, treadmill training is used for aerobic exercise. After 5 days of recovery, mice in the TAE group were subjected to 10-week aerobic exercise. Carotid pressure and cardiac function were examined before mice were executed by Millar catheter and ultrasound, respectively. Muscle mass of gastrocnemius was weighed; cross-sectional area and the number of capillaries of gastrocnemius were detected by HE and immunohistochemistry, respectively. The mRNA and protein levels of VEGF in skeletal muscle were determined by RT-PCR and western blot, respectively. Results. We found that ① 10-week aerobic exercise counteracted hypertension and attenuated cardiac dysfunction in TAC-induced hypertensive mice; ② TAC decreased muscle mass of gastrocnemius and resulted in muscle atrophy, while 10-week aerobic exercise could reserve transverse aortic constriction-induced the decline of muscle mass and muscle atrophy; and ③ TAC reduced the number of capillaries and the protein level of VEGF in gastrocnemius, whereas 10-week aerobic exercise augmented the number of capillaries, the mRNA and protein levels of VEGF in mice were subjected to TAC surgery. Conclusions. This study indicates that 10-week aerobic exercise might fulfill its blood pressure-lowering effect via improving skeletal muscle microcirculation and increasing muscle mass.

scholarly journals Hip Osteonecrosis Is Associated with Increased Plasma IL-33 Level

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Jinhui Ma ◽  
Wanshou Guo ◽  
Zirong Li ◽  
Bailiang Wang ◽  
Shirui Li ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Femoral Head ◽  
Prospective Study ◽  
Family Member ◽  
Healthy Subjects ◽  
Potential Role ◽  
Osteonecrosis Of Femoral Head ◽  
Elisa Kit ◽  
L1 And L2

The recently discovered IL-33 as an IL-1 cytokine family member has been proved to be specifically released from osteonecrotic bones. We aimed to investigate the potential role of IL-33 in the development of osteonecrosis of femoral head (ONFH). Forty patients diagnosed with ONFH and forty age-, sex-, and body mass index- (BMI-) matched healthy subjects were included in this prospective study between March 2016 and September 2016. A commercially available ELISA kit was used to test the level of plasma IL-33. The IL-33 levels were compared among different ARCO stages, CJFH types, and etiology groups. Plasma IL-33 levels were significantly higher in the ONFH patients than that in the control subjects. The levels of IL-33 did not differ significantly among the ONFH patients with different ARCO stages. The IL-33 levels of patients with CJFH type L3 were significantly higher than that of patients with types L1 and L2. No significant differences were observed in IL-33 levels between steroid-induced, alcohol-induced, and idiopathic patients. Our findings seem to indicate that IL-33 effects may be detrimental during ONFH, which appeared to be associated with the prognosis of ONFH. The IL-33 deserves particular attention in the pathogenesis of ONFH.

scholarly journals The Cell Surface Receptors Ror1/2 Control Cardiac Myofibroblast Differentiation

2021 ◽  
Author(s):  
Nicholas W. Chavkin ◽  
Soichi Sano ◽  
Ying Wang ◽  
Kosei Oshima ◽  
Hayato Ogawa ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Fibrosis ◽  
Cardiac Injury ◽  
Pressure Overload ◽  
Orphan Receptor ◽  
Myofibroblast Differentiation ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Cultured Fibroblasts

Background A hallmark of heart failure is cardiac fibrosis, which results from the injury‐induced differentiation response of resident fibroblasts to myofibroblasts that deposit extracellular matrix. During myofibroblast differentiation, fibroblasts progress through polarization stages of early proinflammation, intermediate proliferation, and late maturation, but the regulators of this progression are poorly understood. Planar cell polarity receptors, receptor tyrosine kinase–like orphan receptor 1 and 2 (Ror1/2), can function to promote cell differentiation and transformation. In this study, we investigated the role of the Ror1/2 in a model of heart failure with emphasis on myofibroblast differentiation. Methods and Results The role of Ror1/2 during cardiac myofibroblast differentiation was studied in cell culture models of primary murine cardiac fibroblast activation and in knockout mouse models that underwent transverse aortic constriction surgery to induce cardiac injury by pressure overload. Expression of Ror1 and Ror2 were robustly and exclusively induced in fibroblasts in hearts after transverse aortic constriction surgery, and both were rapidly upregulated after early activation of primary murine cardiac fibroblasts in culture. Cultured fibroblasts isolated from Ror1/2 knockout mice displayed a proinflammatory phenotype indicative of impaired myofibroblast differentiation. Although the combined ablation of Ror1/2 in mice did not result in a detectable baseline phenotype, transverse aortic constriction surgery led to the death of all mice by day 6 that was associated with myocardial hyperinflammation and vascular leakage. Conclusions Together, these results show that Ror1/2 are essential for the progression of myofibroblast differentiation and for the adaptive remodeling of the heart in response to pressure overload.

scholarly journals Increased glucose metabolism in Arid5b−/− skeletal muscle is associated with the down-regulation of TBC1 domain family member 1 (TBC1D1)

2020 ◽  
Vol 53 (1) ◽  
Author(s):  
Yuri Okazaki ◽  
Jennifer Murray ◽  
Ali Ehsani ◽  
Jessica Clark ◽  
Robert H. Whitson ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Plasma Membrane ◽  
Energy Metabolism ◽  
Glucose Metabolism ◽  
Family Member ◽  
Glucose Transporter ◽  
Whole Body ◽  
Domain Family ◽  
Glucose Transporter 1

Abstract Background Skeletal muscle has an important role in regulating whole-body energy homeostasis, and energy production depends on the efficient function of mitochondria. We demonstrated previously that AT-rich interactive domain 5b (Arid5b) knockout (Arid5b−/−) mice were lean and resistant to high-fat diet (HFD)-induced obesity. While a potential role of Arid5b in energy metabolism has been suggested in adipocytes and hepatocytes, the role of Arid5b in skeletal muscle metabolism has not been studied. Therefore, we investigated whether energy metabolism is altered in Arid5b−/− skeletal muscle. Results Arid5b−/− skeletal muscles showed increased basal glucose uptake, glycogen content, glucose oxidation and ATP content. Additionally, glucose clearance and oxygen consumption were upregulated in Arid5b−/− mice. The expression of glucose transporter 1 (GLUT1) and 4 (GLUT4) in the gastrocnemius (GC) muscle remained unchanged. Intriguingly, the expression of TBC domain family member 1 (TBC1D1), which negatively regulates GLUT4 translocation to the plasma membrane, was suppressed in Arid5b−/− skeletal muscle. Coimmunofluorescence staining of the GC muscle sections for GLUT4 and dystrophin revealed increased GLUT4 localization at the plasma membrane in Arid5b−/− muscle. Conclusions The current study showed that the knockout of Arid5b enhanced glucose metabolism through the downregulation of TBC1D1 and increased GLUT4 membrane translocation in skeletal muscle.

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