scholarly journals Impacts of a Specific Cyclooxygenase-2 Inhibitor on Pressure Overload–Induced Myocardial Hypertrophy in Rats

2019 ◽  
Vol 22 (6) ◽  
pp. E432-E437
Author(s):  
Zhixiang Xie ◽  
Shuyin Wang ◽  
Zijing Liang ◽  
Liangbo Zeng ◽  
Rongde Lai ◽  
...  
Keyword(s):  
Myocardial Hypertrophy ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cyclooxygenase 2 ◽  
Inflammatory Factors ◽  
Heart Weight ◽  
Sham Operation ◽  
Surgery Group ◽  
Tnf Α

Objective: The aim of this study was to observe the impacts of the specific cyclooxygenase-2 inhibitor celecoxib on cardiac structures, functions, and inflammatory factors during the process of pressure overload–induced myocardial hypertrophy. Methods: Twenty-four male Sprague Dawley rats were randomly divided into 3 groups: the sham operation group, the surgery group, and the celecoxib group. The model was established according to the abdominal aortic coarctation method. Results: At 16 weeks, rats in the celecoxib group were fed a celecoxib-mixed diet (10 mg/kg) for 8 consecutive weeks. At week 24 after model establishment, the cardiac structures and functions were observed; changes in the levels of tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, prostaglandin E2 (PGE2), C-reactive protein (CRP), and uric acid (UA) were detected; and the contents of Smad1/2/3 proteins (Smad1, Smad2, and Smad3)  were determined. Left ventricular mass index, the heart weight/body weight ratio, and TNF-α, TGF-β, PGE2, CRP, and UA levels of the celecoxib group were all significantly decreased relative to those of the surgery group (P < .05); moreover, the cardiac functions were significantly improved compared to those of the surgery group (P < .05). Conclusions: These results show that inflammatory factors are involved in the myocardial hypertrophy process and that celecoxib may reverse myocardial hypertrophy through a variety of pathways.

Sarcoplasmic reticulum-related changes in cytosolic calcium in pressure-overload-induced feline LV hypertrophy

1993 ◽  
Vol 265 (6) ◽  
pp. H2009-H2016 ◽  
Author(s):  
B. A. Bailey ◽  
S. R. Houser
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Time Course ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Cytosolic Calcium ◽  
Left Ventricular ◽  
Heart Weight ◽  
Body Weight Ratio ◽  
Rest Periods ◽  
Premature Beats

Alterations in Ca2+ homeostasis that involve the sarcoplasmic reticulum (SR) were studied in feline left ventricular (LV) myocytes isolated from hearts with LV hypertrophy induced by slow, progressive pressure overload. At death, severe hypertrophy was evidenced by increased heart weight-to-body weight ratio (8.4 +/- 0.6 vs. 4.2 +/- 0.2 g/kg in controls). Steady-state Ca2+ transients (measured as. indo 1 fluorescence at 410 nm/480 nm; I410/I480) in LV hypertrophy (LVH) myocytes had diminished peak amplitudes (I410/I480 2.28 +/- 0.07 vs. 2.53 +/- 0.07 in controls) and prolonged durations (0.75 +/- 0.03 vs. 0.59 +/- 0.02 s in controls). The magnitude of shortening was reduced and the contractile duration was prolonged in LVH myocytes. The idea that changes in SR function are responsible for these alterations in the Ca2+ transient was tested by studying two aspects of SR-related Ca2+ homeostasis. Restitution of releasable SR Ca2+ was studied by measuring indo 1 transients and contractions during premature beats. The time course of restitution of both the indo 1 transient and contraction of hypertrophy myocytes was significantly slower than in controls. These data suggest that restitution of releasable SR Ca2+ is slowed in hypertrophy myocytes. The reduction of the indo 1 transient and contraction in beats following long rest periods (rest decay) was measured to determine the rate of Ca2+ loss from the SR. Rest decay was significantly (P < 0.05) more pronounced in hypertrophy myocytes, suggesting that Ca2+ loss from the SR is accelerated in these myocytes. (ABSTRACT TRUNCATED AT 250 WORDS)

Echocardiographic assessment of LV hypertrophy and function in aortic-banded mice: necropsy validation

2002 ◽  
Vol 282 (5) ◽  
pp. H1703-H1708 ◽  
Author(s):  
Yulin Liao ◽  
Fuminobu Ishikura ◽  
Shintaro Beppu ◽  
Masanori Asakura ◽  
Seiji Takashima ◽  
...  
Keyword(s):  
Time Course ◽  
Myocardial Hypertrophy ◽  
Systolic Dysfunction ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Sham Operation ◽  
Lung Weight ◽  
Functional Changes ◽  
Heart Mass ◽  
Echocardiographic Assessment

We characterized the time course of the left ventricular (LV) geometric and functional changes after aortic banding, validated them by necropsy, and investigated the sensitivity of echocardiographic findings on LV hypertrophy. C57BL/6 mice were subjected to transverse aortic constriction (TAC) or sham operation; echocardiographic assessments were performed before or at 2, 4, 6, and 11 wk after surgery; and some of the mice were euthanized at the corresponding time points. There was a progressive increase in diastolic posterior wall thickness and LV systolic dimension; the percentage of LV fractional shortening (LV%FS) decreased progressively at 4 wk, whereas these parameters remained stable in sham-operated mice. Echo LV mass and LV%FS correlated well with actual whole heart mass and ratio of lung weight to body weight, respectively ( r = 0.765 and −0.749, respectively; P < 0.0001). These results suggest that the development of myocardial hypertrophy and systolic dysfunction is a time-dependent process. Echocardiographic assessment of myocardial hypertrophy and functional changes correlate well with the actual heart mass and lung mass. Echocardiography is sensitive enough to assess myocardial hypertrophy and heart functional changes induced by pressure overload in mice.

Vitamin C and quinapril abrogate LVH and endothelial dysfunction in aortic-banded guinea pigs

2001 ◽  
Vol 281 (4) ◽  
pp. H1704-H1710 ◽  
Author(s):  
John P. Bell ◽  
Salah I. Mosfer ◽  
Derek Lang ◽  
Francis Donaldson ◽  
Malcolm J. Lewis
Keyword(s):  
Body Weight ◽  
Endothelial Dysfunction ◽  
Vitamin C ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Antioxidant Vitamin ◽  
Ang Ii ◽  
Text Production ◽  
Tnf Α

Left ventricular hypertrophy (LVH) is a cardiovascular risk factor. A possible role for endothelial dysfunction in this condition was investigated in a Dunkin-Hartley guinea pig aortic-banded pressure overload-induced model of LVH. Aortic banding produced significant elevation of fore- and hindlimb blood pressure (BP), heart-to-body weight ratios, plasma angiotensin II (ANG II), endothelin-1 (ET-1), tumor necrosis factor-α (TNF-α) levels, and coronary microvascular endothelial cell (CMEC) NAD(P)H-dependent superoxide (O[Formula: see text]) production, and a significant decrease in basal and stimulated CMEC cGMP levels. Treatment of aortic-banded animals with the angiotensin-converting enzyme inhibitor quinapril and the antioxidant vitamin C, either alone or in combination, did not affect BP but caused a significant inhibition of the increases in the heart-to-body weight ratio, ANG II, ET-1, and TNF-α levels, and O[Formula: see text] production and restored cGMP responses to levels comparable with sham-operated animals. These data suggest that quinapril and vitamin C are capable of inhibiting LVH development due to pressure overload via mechanisms that involve the inhibition of oxidative stress, an improvement in coronary endothelial function, and increased nitric oxide bioavailability.

1181Role of rho-mdia1 signaling to maintain cardiac function in response to pressure overload in mice

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
I Abe ◽  
T Terabayashi ◽  
Y Teshima ◽  
Y Ishii ◽  
M Miyoshi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Actin Dynamics ◽  
Heart Weight ◽  
Sham Operation ◽  
Microarray Gene Expression ◽  
Compensatory Response

Abstract Background Cardiac hypertrophy is a compensatory response to pressure overload that leads to heart failure. Recent studies have shown that Rho signaling has crucial regulatory roles in actin cytoskeleton rearrangement during cardiac hypertrophic responses. Rho is rapidly activated in response to pressure overload, but the mechanisms by which Rho and its downstream proteins control actin dynamics during hypertrophic responses remain unclear. Objective To identify the essential roles of mDia1 (Rho-effector molecule) in pressure overload-induced ventricular hypertrophy. Methods and results Male wild-type (WT) and mDia1-knockout (mDia1KO) mice (10–12 weeks old) were subjected to transverse aortic constriction (TAC) or a sham operation. The heart weight/tibia length ratio, cardiomyocyte cross-sectional area, left ventricular wall thickness, and expression of hypertrophy-specific genes were significantly decreased in mDia1KO mice 3 weeks after TAC, and the mortality rate was higher at 12 weeks. Echocardiography and the pressure-volume loop indicated that mDia1 deletion increased the severity of heart failure 8 weeks after TAC. Microarray gene expression profiling showed that the induction of immediate early genes due to the TAC operation was significantly lower in mDia1KO mice than WT mice, as was the activation of extracellular signal-regulated kinase (ERK) and focal adhesion kinase (FAK). We examined the role of mDia1 in neonatal rat ventricular cardiomyocytes (NRVMs) exposed to mechanical stress. The siRNA-mediated silencing of mDia1 attenuated stretch-induced ERK and FAK phosphorylation, and gene expression of c-fos. Importantly, loss of mDia1 suppressed an increase in the F/G-actin ratio in response to pressure overload in the mice. In addition, increases in nuclear myocardin-related transcription factors (MRTFs) and serum response factor (SRF) were perturbed in response to pressure overload in mDia1KO mice and to mechanical stretch in mDia1 depleted NRVMs. Conclusions Rho-mDia1, through actin dynamics, plays critical roles in pressure overload-induced hypertrophy by regulating ERK and FAK phosphorylation and the transcriptional activity of MRTF-SRF.

Disruption of actin dynamics regulated by Rho effector mDia1 attenuates pressure overload-induced cardiac hypertrophic responses and exacerbates dysfunction

2020 ◽  
Author(s):  
Ichitaro Abe ◽  
Takeshi Terabayashi ◽  
Katsuhiro Hanada ◽  
Hidekazu Kondo ◽  
Yasushi Teshima ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Actin Dynamics ◽  
Heart Weight ◽  
Sham Operation ◽  
Compensatory Response ◽  
Cross Sectional

Abstract Aims Cardiac hypertrophy is a compensatory response to pressure overload, leading to heart failure. Recent studies have demonstrated that Rho is immediately activated in left ventricles after pressure overload and that Rho signalling plays crucial regulatory roles in actin cytoskeleton rearrangement during cardiac hypertrophic responses. However, the mechanisms by which Rho and its downstream proteins control actin dynamics during hypertrophic responses remain not fully understood. In this study, we identified the pivotal roles of mammalian homologue of Drosophila diaphanous (mDia) 1, a Rho-effector molecule, in pressure overload-induced ventricular hypertrophy. Methods and results  Male wild-type (WT) and mDia1-knockout (mDia1KO) mice (10–12 weeks old) were subjected to a transverse aortic constriction (TAC) or sham operation. The heart weight/tibia length ratio, cardiomyocyte cross-sectional area, left ventricular wall thickness, and expression of hypertrophy-specific genes were significantly decreased in mDia1KO mice 3 weeks after TAC, and the mortality rate was higher at 12 weeks. Echocardiography indicated that mDia1 deletion increased the severity of heart failure 8 weeks after TAC. Importantly, we could not observe apparent defects in cardiac hypertrophic responses in mDia3-knockout mice. Microarray analysis revealed that mDia1 was involved in the induction of hypertrophy-related genes, including immediate early genes, in pressure overloaded hearts. Loss of mDia1 attenuated activation of the mechanotransduction pathway in TAC-operated mice hearts. We also found that mDia1 was involved in stretch-induced activation of the mechanotransduction pathway and gene expression of c-fos in neonatal rat ventricular cardiomyocytes (NRVMs). mDia1 regulated the filamentous/globular (F/G)-actin ratio in response to pressure overload in mice. Additionally, increases in nuclear myocardin-related transcription factors and serum response factor were perturbed in response to pressure overload in mDia1KO mice and to mechanical stretch in mDia1 depleted NRVMs. Conclusion  mDia1, through actin dynamics, is involved in compensatory cardiac hypertrophy in response to pressure overload.

scholarly journals QiShenYiQi Pill Improves Myocardial Hypertrophy Caused by Pressure Overload in Rats

2020 ◽  
Author(s):  
Shichao Lv ◽  
Qiang Wang ◽  
Meifang Wu ◽  
Meng Li ◽  
Xiaojing Wang ◽  
...  
Keyword(s):  
Protein Expression ◽  
Mechanism Of Action ◽  
Aortic Coarctation ◽  
Myocardial Hypertrophy ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Control Group ◽  
Sham Operation ◽  
Tgf Beta ◽  
Abdominal Aortic

Abstract Background: QiShenYiQi pill (QSYQ), a traditional Chinese medicine, is widely used in the treatment of cardiovascular diseases, but its specific mechanism of action is still unclear. In the current study, we investigated the effect of QSYQ on myocardial hypertrophy in rats by partial abdominal aortic coarctation, and explored its mechanism of action.Methods: Wistar rats underwent the partial abdominal aortic coarctation were randomized into three groups: model, valsartan and QSYQ groups. And we treated rats which were sham operation as control group. Rats were euthanized at 4 and 8 weeks, and we weighed rat body mass, heart mass, and left ventricular mass. Myocardium sections were stained with hematoxylin and eosin (H&E) and Masson trichrome. Myocardial TGF- beta 1 and CTGF protein expression was detected by immunohistochemistry, and myocardial TGF-b1 and CTGF mRNA expression was detected by real-time qPCR. Results: QSYQ reduced HMI, LVMI and CVF, improved the changes of myocardial pathology, and reduced the degree of myocardial hypertrophy. After 4 weeks, QSYQ inhibited the mRNA and protein expression of TGF- beta 1 and CTGF. In addition, after 8 weeks, QSYQ reduced the positive area of TGF- beta 1 protein, and its effect is better than that of valsartan. Conclusions: QSYQ can effectively improve the degree of myocardial hypertrophy in the pressure overload rats, which is related to the mechanism of regulation of TGF- beta 1 and CTGF.

Duration of pressure overload alters regression of coronary circulation abnormalities

1990 ◽  
Vol 258 (6) ◽  
pp. H1753-H1760 ◽  
Author(s):  
N. Ito ◽  
S. Isoyama ◽  
M. Kuroha ◽  
T. Takishima
Keyword(s):  
Coronary Circulation ◽  
Myocardial Hypertrophy ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Dry Weight ◽  
Coronary Perfusion Pressure ◽  
Left Ventricular ◽  
Coronary Perfusion ◽  
Crystalloid Solution ◽  
Tissue Weight

Using a rat model of ascending aortic banding and debanding, we examined how the duration of pressure overload affects reversibility in coronary circulation abnormalities after relief of pressure overload. Four-week banding increased left ventricular dry weight-to-body weight ratio to 158 +/- 8% of that of sham-operated controls. In isolated nonworking hearts perfused with crystalloid solution, peak mean coronary flow rate (CFR) was measured after brief ischemia. CFR and CFR/dry tissue weight significantly decreased (75 +/- 5 and 54 +/- 3% of that of controls at 100 mmHg of coronary perfusion pressure; 75 +/- 5 and 54 +/- 4% at 150 mmHg, respectively). Four weeks after debanding was performed, CFR and CFR/dry tissue weight increased to similar levels in controls. On the other hand, 10-wk banding produced the same degree of myocardial hypertrophy and decreases in CFR and CFR/dry tissue weight as in 4-wk banded rats. Four weeks after debanding was performed, CFR had not changed. CFR/dry tissue weight increased because of regression of myocardial hypertrophy but was significantly lower than that in rats debanded after 4 wk of banding. Thus the duration of pressure overload does not affect the degree of coronary circulation abnormalities in the progression process but does affect it in the regression process.

Abstract 15687: Loss of Tribbles 3 (TRIB3) Attenuates Pressure-Overload Induced Myocardial Hypertrophy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Eltyeb Abdelwahid ◽  
Rongxue Wu ◽  
Amy K Rines ◽  
Hossein Ardehali
Keyword(s):  
Cardiac Hypertrophy ◽  
Wall Thickness ◽  
Pressure Overload ◽  
Cellular Metabolism ◽  
Left Ventricular ◽  
Left Ventricular Wall ◽  
Heart Weight ◽  
Sham Operation ◽  
Ventricular Wall ◽  
Exact Function

Introduction: Tribbles 3 (TRIB3) is a pseudokinase that regulates several biological functions such as cell proliferation and differentiation through its role in cellular metabolism. TRIB3 expression is modulated by various signals such as endoplasmic reticulum (ER) stress, nutrient availability, and insulin. The exact function of TRIB3 in the heart is largely unknown. We hypothesized that loss of TRIB3 protects against cardiac hypertrophy through its role in the regulation of cellular metabolism. Results: To elucidate the role of TRIB3 loss in the heart, we generated TRIB3 knock-out (KO) mice. The animals were then subjected to transverse aortic constriction (TAC) and sham-surgery control. In the sham operation groups, there was no hypertrophy in both TRIB3-/- and Wild type (WT) age matched control mice. WT mice subjected to TAC (WT-TAC) showed cardiac hypertrophy evidenced by increased heart weight/body weight, increased left ventricular wall thickness and increased cardiomyocyte cross-sectional area. These hypertrophic findings were significantly reduced in TRIB3 KO-TAC hearts (P<0.05). Echocardiographic analysis revealed increased diastolic interventricular septum wall (IVSd), increased left ventricular wall posterior wall thickness (LVPWd) and decreased fractional shortening (FS) in WT-TAC mice, however these changes were significantly blocked in TRIB3 KO-TAC group suggesting that TAC-induced left ventricular hypertrophy and dysfunction was attenuated in TRIB3 KO mice (P<0.05). The blunted response to hypertrophy seen in TRIB3 KO-TAC group was further demonstrated by the significant decrease in mRNA expression of myocardial hypertrophic markers (ANP, BNP and MHC) in TRIB3 KO-TAC hypertrophied left ventricles compared to WT-TAC control subjects (P<0.05). Furthermore, our data indicated increased TRIB3 expression in the WT-TAC hypertrophied left ventricles compared to WT-Sham group (P<0.05). Conclusions: The present study demonstrated that TRIB3 expression is promoted in hypertrophied hearts. TRIB3 deletion suppresses cardiac pressure overload-induced hypertrophy. Thus, TRIB3 is a novel target that plays a role in cardiac hypertrophy and maladaptation following pressure overload.

Cardiac myocyte volume, Ca2+ fluxes, and sarcoplasmic reticulum loading in pressure-overload hypertrophy

1997 ◽  
Vol 272 (5) ◽  
pp. H2425-H2435 ◽  
Author(s):  
L. M. Delbridge ◽  
H. Satoh ◽  
W. Yuan ◽  
J. W. Bassani ◽  
M. Qi ◽  
...  
Keyword(s):  
Steady State ◽  
Sarcoplasmic Reticulum ◽  
Laser Scanning ◽  
Cardiac Myocyte ◽  
Membrane Surface ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Heart Weight ◽  
The Relationship

Alterations in cellular Ca2+ transport and excitation-contraction coupling may contribute to dysfunction in cardiac hypertrophy. Left ventricular myocytes were isolated from rat hearts after 15-18 wk of suprarenal abdominal aortic banding to evaluate the hypothesis that hypertrophy alters the relationship between Ca2+ current (ICa) and sarcoplasmic reticulum (SR) Ca2+ load during steady-state voltage-clamp depolarization. Mean arterial pressure (MAP) and heart weight-to-body weight ratio of banded (B) animals were significantly higher than in control or sham-operated animals (C). Isolated myocyte dimensions and volume increased in parallel with whole heart hypertrophy and elevation in MAP. However, the relationship between membrane surface area (measured by capacitance) and cell volume (measured by laser scanning confocal microscopy) was unaltered (C: 8.9 +/- 0.3; B: 8.5 +/- 0.4 pF/pl). No differences in the voltage dependence of ICa activation, steady-state inactivation, or recovery from inactivation were detected between C and B myocytes. Maximal ICa density for the two groups was also not different either under basal conditions (C: 4.28 +/- 0.98; B: 4.57 +/- 0.60 pA/pF) or in the presence of 1 microM isoproterenol (C: 16.6 +/- 2.3; B: 16.5 +/- 2.3 pA/pF). The fraction of Ca2+ released from the SR by a single twitch was 55.4 +/- 9.4% in C and 37.1 +/- 6.9% in B (not significantly different). Steady-state Ca2+ influx during a twitch was calculated in units of micromoles per liter of nonmitochondrial volume from the integral of ICa (C: 13.4 +/- 0.7 microM; B: 13.3 +/- 0.8 microM). The SR Ca2+ load was similarly calculated by integration of Na+/Ca2+ exchange current induced by rapid caffeine application (C: 140 +/- 9 microM; B: 169 +/- 18 microM). We conclude that significant cellular hypertrophy is associated with proportional increases in sarcolemmal ICa influx, SR Ca2+ loading, and the amount of SR Ca2+ released in this model of pressure overload.

P4997Raf kinase inhibitor protein of the bone marrow contributes to cardiac fibrogenesis in pressure-overloaded myocardium

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Kazakov ◽  
R Hall ◽  
S N Weber ◽  
A Trouvain ◽  
F Lammert ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Kinase Inhibitor ◽  
Systolic Pressure ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Heart Weight ◽  
Sham Operation ◽  
Ros Production ◽  
Myocardial Remodeling ◽  
Inhibitor Protein

Abstract Background Raf Kinase Inhibitor Protein (RKIP) regulates myocardial remodeling under conditions of enhanced myocardial oxidative stress in pressure-overloaded left ventricle (LV) modulating myocardial production of reactive oxygen species (ROS). A second mode of action may be the mobilization of circulating fibroblasts (fibrocytes) from the bone-marrow (BM). However the underlying mechanisms are incompletely understood. Methods and results To further characterize the role of RKIP in BM cells for myocardial remodeling 10-week-old wild-type (WT) C57BL/6N mice were subjected to transplantation of bone marrow (BMT) from 10-week-old C57BL/6-RKIP-deficient (RKIP−/−) N or WT C57BL/6N mice expressing green fluorescent protein (GFP)+ ubiquitously. 28 days later, transverse aortic constriction (TAC, 360 μm) or SHAM-operation was performed. 5 weeks post TAC, LV systolic pressure (LVSP) and heart weight to tibia length ratio were significantly increased in both types of BMT, compared with corresponding SHAM. Increased afterload elicited myocardial fibrosis as assessed by picrosirius red staining (WT/WT SHAM 15±2.5%, WT/WT TAC 21.3±1.4%, p<0.05; RKIP−/−/WT SHAM 17±2%, RKIP−/−/WT TAC 18±3%, p=ns) and significantly increased the number of LV fibroblasts per mm2 estimated by immunostaining for intracellular fibronectin, which were further reduced by transplantation of RKIP−/−N BM (WT/WT SHAM 5499±313, WT/WT TAC 7493±741 per mm2, p<0.05; RKIP−/−/WT SHAM 5737±259, RKIP−/−/WT TAC 5282±551, per mm2, p=ns). Moreover, transplantation of RKIP−/−N BM significantly diminished the number of circulating BM-derived GFP+ fibroblasts in the peripheral blood and LV myocardium during pressure overload (WT/WT SHAM 961±129, WT/WT TAC 2326±273 per mm2, p<0.05; RKIP−/−/WT SHAM 1041±209, RKIP−/−/WT TAC 1518±107, per mm2, p=ns). The myocardial redox status was assessed by the co-immunostaining for ROS production marker 8-hydroxyguanosin (8-dOHG), cardiomyocyte marker α-sarcomeric actin and fibroblast marker intracellular fibronectin. Pressure overload during 5 weeks significantly increased the percentages of 8-dOHG+cardiomyocytes (WT/WT SHAM 34±9%, WT/WT TAC 63±6%, p<0.05; RKIP−/−/WT SHAM 29±6%, RKIP−/−/WT TAC 31±8%, p=ns) and 8-dOHG+fibroblasts (WT/WT SHAM 57±6%, WT/WT TAC 73±4%, p<0.05; RKIP−/−/WT SHAM 58±2%, RKIP−/−/WT TAC 58±7%, p=ns) in mice transplanted with WT BM but not with RKIP−/−N BM. Conclusions In pressure-overload induced enhanced myocardial ROS production, deficiency of RKIP-expression in the bone marrow abrogates left ventricular fibrosis by reduction of myocardial ROS production and mobilization of BM-derived fibroblasts. These findings suggest that the function of RKIP in the bone marrow may be important for maladaptive myocardial remodelling. Acknowledgement/Funding Deutsche Forschungsgemeinschaft: KA4024/3-1, SFB TRR219; Saarland University HOMFOR, Dr. Marija Orlovich foundation, Corona foundation s199/10060/2014

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