Abstract 15737: Deficiency of Mitochondrial Calcium Uniporter Protects Mouse Hearts From Iron Overload by Attenuating Ferroptosis

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Nadezhda Fefelova ◽  
Suwakon Wongjaikam ◽  
Natthaphat Siri-Angkul ◽  
Judith Gwathmey ◽  
Nipon Chattipakorn ◽  
...  
Keyword(s):  
Iron Overload ◽  
Lipid Oxidation ◽  
Cardiac Dysfunction ◽  
Heart Function ◽  
Systolic Function ◽  
Hereditary Hemochromatosis ◽  
Dead Cell ◽  
Dependent Manner ◽  
Cellular Mechanisms ◽  
Oxidation Level

Iron (Fe) plays essential roles in many physiological processes. Hereditary hemochromatosis and frequent blood transfusions result in iron overload (IO) and dysfunction of iron-deposited organs including the heart. Although IO-induced cardiomyopathy remains a significant clinical challenge, the underlying mechanism is not well defined. In the present study, we aim to assess the involvement of the mitochondrial Ca uniporter (mCU) in IO-induced cardiac contractile dysfunction and ferroptosis. In a chronic IO model, after receiving Fe (dextran, i.p. 0.6 mg/g, 3 days/wk) for 6 weeks, systolic function (LVEF and LVFS) was reduced in mCU +/+ (WT) compared to mCU -/- (mCU KO). This observation was confirmed in isolated ventricular myocytes where we similarly detected a significant decrease in cell shortening in WT, but not mCU KO myocytes. We found lower Fe levels in mitochondria from mCU KO myocytes compared to WT, while observing the same level of Fe deposition in heart tissue from both groups. The mitochondrial ROS level was lower in mCU KO myocytes vs. WT. Long term cardiac dysfunction may result in myocyte cell death, however, we did not detect apoptosis (TUNEL) in either mCU KO or in WT hearts with cardiac dysfunction after chronic IO. The lipid oxidation level was increased with Fe load suggesting ferroptosis may be involved in IO-induced cardiomyopathy, which was supported by the observation that administration of the selective ferroptosis inhibitor ferrostatin-1 reduced lipid oxidation (4-HNE) and maintained heart function. To further determine the role of mCU in IO-mediated ferroptosis in the heart, we used isolated myocytes from WT and mCU KO and conducted Live/Dead cell viability assays. While Fe (FAC, 0.1-5 mM) induced ferroptosis in a dose-dependent manner, it was prevented by ferrostatin-1 (10 μM), the Fe chelator 2,2'-bipyridyl (2 mM), and MitoTEMPO (5 μM), respectively. Fe-induced ferroptosis in mCU KO myocytes did not occur while the lipid oxidation level (Liperfluo) remained low. In conclusion, mitochondrial Fe uptake, presumably mediated by mCU, accounts for the molecular/cellular mechanisms for Fe-induced myocyte ferroptosis and cardiomyopathy. Cardiac-specific deficiency of mCU prevents the development of Fe induced cardiomyopathy.

scholarly journals Loss of Apelin Augments Angiotensin II-Induced Cardiac Dysfunction and Pathological Remodeling

2019 ◽  
Vol 20 (2) ◽  
pp. 239 ◽  
Author(s):  
Teruki Sato ◽  
Ayumi Kadowaki ◽  
Takashi Suzuki ◽  
Hiroshi Ito ◽  
Hiroyuki Watanabe ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Angiotensin Converting Enzyme ◽  
Knockout Mice ◽  
Cardiac Dysfunction ◽  
Transforming Growth Factor ◽  
Heart Function ◽  
Dependent Manner ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Pathological Remodeling

Apelin is an inotropic and cardioprotective peptide that exhibits beneficial effects through activation of the APJ receptor in the pathology of cardiovascular diseases. Apelin induces the expression of angiotensin-converting enzyme 2 (ACE2) in failing hearts, thereby improving heart function in an angiotensin 1–7-dependent manner. Whether apelin antagonizes the over-activation of the renin–angiotensin system in the heart remains elusive. In this study we show that the detrimental effects of angiotensin II (Ang II) were exacerbated in the hearts of aged apelin-gene-deficient mice. Ang II-mediated cardiac dysfunction and hypertrophy were augmented in apelin knockout mice. The loss of apelin increased the ratio of angiotensin-converting enzyme (ACE) to ACE2 expression in the Ang II-stressed hearts, and Ang II-induced cardiac fibrosis was markedly enhanced in apelin knockout mice. mRNA expression of pro-fibrotic genes, such as transforming growth-factor beta (TGF-β) signaling, were significantly upregulated in apelin knockout hearts. Consistently, treatment with the ACE-inhibitor Captopril decreased cardiac contractility in apelin knockout mice. In vitro, apelin ameliorated Ang II-induced TGF-β expression in primary cardiomyocytes, accompanied with reduced hypertrophy. These results provide direct evidence that endogenous apelin plays a crucial role in suppressing Ang II-induced cardiac dysfunction and pathological remodeling.

Abstract P227: Elevated Plasma Activin A Levels Impairs Global Longitudinal Strain In The Heart During Pregnancy

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Bhavisha A Bakrania ◽  
Sajid Shahul ◽  
Michael E Hall ◽  
Joey P Granger
Keyword(s):  
Blood Pressure ◽  
Cardiac Dysfunction ◽  
Longitudinal Strain ◽  
Tissue Injury ◽  
Systolic Function ◽  
Blood Pressure Measurement ◽  
Global Longitudinal Strain ◽  
Activin A ◽  
Inflammatory Factors ◽  
Dependent Manner

Preeclampsia (PE) is a disorder prevalent in 3-8% of pregnancies, characterized by maternal hypertension, endothelial dysfunction and impaired cardiac function. PE develops in response to impaired spiral artery remodeling, leading to poor perfusion of the placenta. The ischemic placenta releases anti-angiogenic and pro-inflammatory factors into the maternal circulation leading to widespread endothelial activation. Studies have also shown that PE women exhibit decreased cardiac global longitudinal strain (GLS), a sensitive measure of systolic function that indicates fibrosis and tissue injury. Importantly, GLS remains impaired postpartum, when blood pressure has returned to normal, suggesting that placental factors could play a role in the development of cardiac dysfunction in PE. A recent study showed Activin A, a pro-fibrotic factor that is released by the placenta, is increased during PE and is predictive of impaired GLS one year postpartum. PE is a multifaceted disease, and whether increased circulating Activin A alone induces cardiac dysfunction is not known. We hypothesized that chronic excess levels of Activin A during pregnancy induces cardiac dysfunction. To address this, rats were administered vehicle ( n =6) or Activin A ( n =6/group; A2, 1.9μg/day, A3, 3 μg/day, A4, 6μg/day) via osmotic pump on gestational day (GD) 14. All animals had an indwelling carotid catheter placed on GD 18, followed by a comprehensive echocardiography assessment and blood pressure measurement on GD19. Activin A infusion resulted in significant increases in circulating Activin A in all treated groups (Vehicle, 585±47 pg/mL, A2, 2022±695 pg/mL, A3, 2511±409 pg/mL, A4, 2801±410 pg/mL, P<0.01). At higher doses, Activin A infusion was associated with significantly impaired GLS (Vehicle, -22.1±0.8 %, A3, -16.7±1.87 %, P<0.01, A4, -14.7±1.14 %, P<0.01). Mean arterial pressure was not significantly different between groups. These findings suggest that Activin A causes cardiac dysfunction in a dose dependent manner and may induce impaired GLS during pregnancy, independent of increases in blood pressure. This model could be useful in understanding the mechanisms of Activin A and whether blockade of this factor could improve outcomes.

Magnesium attenuates isoproterenol-induced acute cardiac dysfunction and β-adrenergic desensitization

2007 ◽  
Vol 292 (3) ◽  
pp. H1593-H1599 ◽  
Author(s):  
Yin-Tie Jin ◽  
Naoyuki Hasebe ◽  
Tomoyuki Matsusaka ◽  
Shunsuke Natori ◽  
Takafumi Ohta ◽  
...  
Keyword(s):  
Dose Response ◽  
Large Dose ◽  
Cardiac Dysfunction ◽  
Systolic Function ◽  
Lipid Peroxide ◽  
Myocardial Damage ◽  
Left Ventricular ◽  
Compensatory Mechanism ◽  
Dependent Manner ◽  
Small Doses

Sympathetic nervous activation is a crucial compensatory mechanism in heart failure. However, excess catecholamine may induce cardiac dysfunction and β-adrenergic desensitization. Although magnesium is known to be a cardioprotective agent, its beneficial effects on acute cardiac dysfunction remain to be elucidated. We examined the effects of magnesium on left ventricular (LV) dysfunction induced by a large dose of isoproterenol in dogs. Sixteen anesthetized dogs underwent a continuous infusion of isoproterenol (1 μg·kg−1·min−1) with or without a magnesium infusion (1 mg·kg−1·min−1). The dose response to small doses of isoproterenol (0.025–0.2 μg·kg−1·min−1) was tested hourly. A large dose of isoproterenol decreased LV systolic function, increased the time constant of LV isovolumic relaxation, and suppressed the dose response to small doses of isoproterenol in a time-dependent manner. Magnesium significantly attenuated isoproterenol-induced LV systolic and diastolic dysfunction and preserved the dose response to isoproterenol. Serum-ionized calcium significantly decreased with a large dose of isoproterenol but was fully maintained at baseline level with magnesium. A large dose of isoproterenol increased serum lipid peroxide levels and serological markers of myocardial damage, which were significantly suppressed by magnesium. In conclusion, magnesium significantly attenuated excess isoproterenol-induced acute cardiac dysfunction and β-adrenergic desensitization.

Delayed expression of cytokines after reperfused myocardial infarction: possible trigger for cardiac dysfunction and ventricular remodeling

2007 ◽  
Vol 293 (5) ◽  
pp. H3014-H3019 ◽  
Author(s):  
Cécile Moro ◽  
Marie-Gabrielle Jouan ◽  
Andry Rakotovao ◽  
Marie-Claire Toufektsian ◽  
Olivier Ormezzano ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Ventricular Remodeling ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Cellular Mechanisms ◽  
Artery Ligation ◽  
Tnf Α

Previous studies have shown that 1 wk after permanent coronary artery ligation in rats, some cellular mechanisms involving TNF-α occur and contribute to the development of cardiac dysfunction and subsequent heart failure. The aim of the present study was to determine whether similar phenomena also occur after ischemia-reperfusion and whether cytokines other than TNF-α can also be involved. Anesthetized male Wistar rats were subjected to 1 h coronary occlusion followed by reperfusion. Cardiac geometry and function were assessed by echocardiography at days 5, 7, 8, and 10 postligation. Before death, heart function was assessed in vivo under basal conditions, as well as after volume overload. Finally, hearts were frozen for histoenzymologic assessment of infarct size and remodeling. The profile of cardiac cytokines was determined by ELISA and ChemiArray on heart tissue extracts. As expected, ischemia-reperfusion induced a progressive remodeling of the heart, characterized by left ventricular free-wall thinning and cavity dilation. Heart function was also decreased in ischemic rats during the first week after surgery. Interestingly, a transient and marked increase in TNF-α, IL-1β, IL-6, cytokine-induced neutrophil chemoattractant (CINC) 2, CINC3, and macrophage inflammatory protein-3α was also observed in the myocardium of myocardial ischemia (MI) animals at day 8, whereas the expression of anti-inflammatory interleukins IL-4 and IL-10 remained unchanged. These results suggest that overexpression of proinflammatory cytokines occurring during the first week after ischemia-reperfusion may play a role in the adaptative process in the myocardium and contribute to early dysfunction and remodeling.

scholarly journals Interplay Between Iron Overload and Osteoarthritis: Clinical Significance and Cellular Mechanisms

2022 ◽  
Vol 9 ◽  
Author(s):  
Chenhui Cai ◽  
Wenhui Hu ◽  
Tongwei Chu
Keyword(s):  
Iron Overload ◽  
Molecular Mechanisms ◽  
Hereditary Hemochromatosis ◽  
Basic Research ◽  
Joint Inflammation ◽  
Cartilage Degradation ◽  
Negative Influence ◽  
Joint Disease ◽  
Cellular Mechanisms ◽  
Synovial Tissues

There are multiple diseases or conditions such as hereditary hemochromatosis, hemophilia, thalassemia, sickle cell disease, aging, and estrogen deficiency that can cause iron overload in the human body. These diseases or conditions are frequently associated with osteoarthritic phenotypes, such as progressive cartilage degradation, alterations in the microarchitecture and biomechanics of the subchondral bone, persistent joint inflammation, proliferative synovitis, and synovial pannus. Growing evidences suggest that the conditions of pathological iron overload are associated with these osteoarthritic phenotypes. Osteoarthritis (OA) is an important complication in patients suffering from iron overload-related diseases and conditions. This review aims to summarize the findings and observations made in the field of iron overload-related OA while conducting clinical and basic research works. OA is a whole-joint disease that affects the articular cartilage lining surfaces of bones, subchondral bones, and synovial tissues in the joint cavity. Chondrocytes, osteoclasts, osteoblasts, and synovial-derived cells are involved in the disease. In this review, we will elucidate the cellular and molecular mechanisms associated with iron overload and the negative influence that iron overload has on joint homeostasis. The promising value of interrupting the pathologic effects of iron overload is also well discussed for the development of improved therapeutics that can be used in the field of OA.

A Cuticle Collagen Encoded by the lon-3 Gene May Be a Target of TGF-β Signaling in Determining Caenorhabditis elegans Body Shape

Genetics ◽  
2002 ◽  
Vol 162 (4) ◽  
pp. 1631-1639
Author(s):  
Yo Suzuki ◽  
Gail A Morris ◽  
Min Han ◽  
William B Wood
Keyword(s):  
Caenorhabditis Elegans ◽  
Body Shape ◽  
Small Body ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Cellular Mechanisms ◽  
C Elegans ◽  
Gene Expression Analyses ◽  
Dose Dependent

Abstract The signaling pathway initiated by the TGF-β family member DBL-1 in Caenorhabditis elegans controls body shape in a dose-dependent manner. Loss-of-function (lf) mutations in the dbl-1 gene cause a short, small body (Sma phenotype), whereas overexpression of dbl-1 causes a long body (Lon phenotype). To understand the cellular mechanisms underlying these phenotypes, we have isolated suppressors of the Sma phenotype resulting from a dbl-1(lf) mutation. Two of these suppressors are mutations in the lon-3 gene, of which four additional alleles are known. We show that lon-3 encodes a collagen that is a component of the C. elegans cuticle. Genetic and reporter-gene expression analyses suggest that lon-3 is involved in determination of body shape and is post-transcriptionally regulated by the dbl-1 pathway. These results support the possibility that TGF-β signaling controls C. elegans body shape by regulating cuticle composition.

scholarly journals Diastolic dysfunction in a pre-clinical model of diabetes is associated with changes in the cardiac non-myocyte cellular composition

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Charles D. Cohen ◽  
Miles J. De Blasio ◽  
Man K. S. Lee ◽  
Gabriella E. Farrugia ◽  
Darnel Prakoso ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Diastolic Dysfunction ◽  
Systolic Function ◽  
Cardiac Fibroblasts ◽  
Detailed Examination ◽  
Diabetic Mice ◽  
Cellular Mechanisms ◽  
Clinical Model ◽  
Cardiac Ventricles

Abstract Background Diabetes is associated with a significantly elevated risk of cardiovascular disease and its specific pathophysiology remains unclear. Recent studies have changed our understanding of cardiac cellularity, with cellular changes accompanying diabetes yet to be examined in detail. This study aims to characterise the changes in the cardiac cellular landscape in murine diabetes to identify potential cellular protagonists in the diabetic heart. Methods Diabetes was induced in male FVB/N mice by low-dose streptozotocin and a high-fat diet for 26-weeks. Cardiac function was measured by echocardiography at endpoint. Flow cytometry was performed on cardiac ventricles as well as blood, spleen, and bone-marrow at endpoint from non-diabetic and diabetic mice. To validate flow cytometry results, immunofluorescence staining was conducted on left-ventricles of age-matched mice. Results Mice with diabetes exhibited hyperglycaemia and impaired glucose tolerance at endpoint. Echocardiography revealed reduced E:A and e’:a’ ratios in diabetic mice indicating diastolic dysfunction. Systolic function was not different between the experimental groups. Detailed examination of cardiac cellularity found resident mesenchymal cells (RMCs) were elevated as a result of diabetes, due to a marked increase in cardiac fibroblasts, while smooth muscle cells were reduced in proportion. Moreover, we found increased levels of Ly6Chi monocytes in both the heart and in the blood. Consistent with this, the proportion of bone-marrow haematopoietic stem cells were increased in diabetic mice. Conclusions Murine diabetes results in distinct changes in cardiac cellularity. These changes—in particular increased levels of fibroblasts—offer a framework for understanding how cardiac cellularity changes in diabetes. The results also point to new cellular mechanisms in this context, which may further aid in development of pharmacotherapies to allay the progression of cardiomyopathy associated with diabetes.

NRSF-GNAO1-CaMK2 axis exacerbates cardiac remodeling and progresses heart failure by impairing Ca2+ homeostasis

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
H Inazumi ◽  
K Kuwahara ◽  
Y Kuwabara ◽  
Y Nakagawa ◽  
H Kinoshita ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Knockout Mice ◽  
Cardiac Remodeling ◽  
Cardiac Dysfunction ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Systolic Function ◽  
Dominant Negative Mutant ◽  
Funding Source

Abstract Background In the development of heart failure, pathological intracellular signaling reactivates fetal cardiac genes, which leads to maladaptive remodeling and cardiac dysfunction. We previously reported that a transcriptional repressor, neuron restrictive silencer factor (NRSF) represses fetal cardiac genes and maintains normal cardiac function under normal conditions, while hypertrophic stimuli de-repress this NRSF mediated repression via activation of CaMKII. Molecular mechanisms by which NRSF maintains cardiac systolic function remains to be determined, however. Purpose To elucidate how NRSF maintains normal cardiac homeostasis and identify the novel therapeutic targets for heart failure. Methods and results We generated cardiac-specific NRSF knockout mice (NRSF cKO), and found that these NRSF cKO showed cardiac dysfunction and premature deaths accompanied with lethal arrhythmias, as was observed in our previously reported cardiac-specific dominant-negative mutant of NRSF transgenic mice (dnNRSF-Tg). By cDNA microarray analysis of dnNRSF-Tg and NRSF-cKO, we identified that expression of Gnao1 gene encoding Gαo, a member of inhibitory G proteins, was commonly increased in ventricles of both types of mice. ChIP-seq analysis, reporter assay and electrophoretic mobility shift assay identified that NRSF transcriptionally regulates Gnao1 gene expression. Genetic Knockdown of Gαo in dnNRSF-Tg and NRSF-cKO by crossing these mice with Gnao1 knockout mice ameliorated the reduced systolic function, increased arrhythmogenicity and reduced survival rates. Transgenic mice expressing a human GNAO1 in their hearts (GNAO1-Tg) showed progressive cardiac dysfunction with cardiac dilation. Ventricles obtained from GNAO1-Tg have increased phosphorylation level of CaMKII and increased expression level of endogenous mouse Gnao1 gene. These data suggest that increased cardiac expression of Gαo is sufficient to induce pathological Ca2+-dependent signaling and cardiac dysfunction, and that Gαo forms a positive regulatory circuit with CaMKII and NRSF. Electrophysiological analysis in ventricular myocytes of dnNRSF-Tg revealed that impaired Ca2+ handling via alterations in localized L-type calcium channel (LTCC) activities; decreased T-tubular and increased surface sarcolemmal LTCC activities, underlies Gαo-mediated cardiac dysfunction. Furthermore, we also identified increased expression of Gαo in ventricles of two different heart failure mice models, mice with transverse aortic constriction and mice carrying a mutant cardiac troponin T, and confirmed that genetic reduction of Gαo prevented the progression of cardiac dysfunction in both types of mice. Conclusions Increased expression of Gαo, induced by attenuation of NRSF-mediated repression forms a pathological circuit via activation of CaMKII. This circuit exacerbates cardiac remodeling and progresses heart failure by impairing Ca2+ homeostasis. Gαo is a potential therapeutic target for heart failure. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Grants-in –Aid for Scientific Research from the Japan Society for the Promotion of Science

P1-23 G-CSF AUGMENTS IRON OVERLOAD CARDIAC DYSFUNCTION AND PROMOTES INFLAMMATORY DEPENDENT CARDIAC THROMBOSIS IN MICE

2007 ◽  
Vol 122 ◽  
pp. S67-S68
Author(s):  
Wei-Shiuang Lien ◽  
Heng Lin ◽  
Kai-Cheng Yang ◽  
Pei-Chi Kim ◽  
Ching-Feng Chen
Keyword(s):  
Iron Overload ◽  
Cardiac Dysfunction

Abstract 17375: In Utero Particulate Matter Exposure Produces Heart Failure and Electrical Remodeling at Adulthood

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Victor P Long ◽  
Vineeta Tanwar ◽  
Matthew W Gorr ◽  
Stephen H Baine ◽  
Ingrid M Bonilla ◽  
...  
Keyword(s):  
Particulate Matter ◽  
Cardiac Dysfunction ◽  
Systolic Function ◽  
In Utero ◽  
In Utero Exposure ◽  
Electrical Remodeling ◽  
Morphological Alterations ◽  
Adult Mice ◽  
Significant Prolongation ◽  
Electrophysiological Recordings

Introduction: In utero exposure to particulate matter through perinatal development has been demonstrated to produce cardiac dysfunction during adulthood. It is unknown what effect exposure to air pollution during the in utero period alone has on cardiac dysfunction and electrical remodeling in adulthood. We tested the hypothesis that adult mice exposed to concentrated particulate matter in utero would demonstrate global cardiac dysfunction as well as cellular electrical remodeling at adulthood. Methods: Female FVB mice were exposed either to filtered air (FA) or particulate matter with diameter less than 2.5 μm (PM2.5) at a concentration of ~ 51.69 μg/m3 for 6 h/day, 7 days/wk (consistent with exposure in a large metropolitan city) beginning at plug formation throughout pregnancy. Cardiac function was assessed via ECHO in male offspring at 12 wks of age, followed by sacrifice and isolation of ventricular cardiomyocytes from both groups of mice for electrophysiological recordings. Results: ECHO identified increased LVESd (2.25 ± 0.20 FA, 2.61 ± 0.35 PM2.5, P=0.0001) and LVEDd (3.89 ± 0.03 FA, 3.99 ± 0.038 PM2.5, P=0.04) dimensions and reduced PWTs (1.40 ± 0.05 FA, 1.26 ± 0.04 PM2.5, P=0.04) in mice exposed in utero to PM2.5. Morphological alterations were associated with lower systolic function as indicated by reduced fractional shortening% (43.6 ± 2.1 FA, 33.2 ± 1.6 PM2.5, P=0.0009) in PM2.5 exposed mice compared to FA controls. Electrophysiological recordings revealed significant prolongation of the action potential at 90% repolarization (APD90) in PM2.5 exposed mice compared to FA. (FIGURE) Conclusions: In utero exposure to relevant levels of particulate matter results in dilated cardiomyopathy and electrical remodeling. Future studies are warranted to determine the causes of, and the exposure thresholds resulting in this adverse cardiac remodeling.

Sign in / Sign up

Export Citation Format

Share Document