scholarly journals Sildenafil Recovers Burn-Induced Cardiomyopathy

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1393 ◽  
Author(s):  
Jake J. Wen ◽  
Claire Cummins ◽  
Ravi S. Radhakrishnan
Keyword(s):  
Gene Expression ◽  
Cardiac Fibrosis ◽  
Burn Injury ◽  
Heart Function ◽  
Mrna Level ◽  
Total Body Surface Area ◽  
Left Ventricular ◽  
Cgmp Level ◽  
Sod Activity ◽  
Heart Dysfunction

Background: Severe burn injury initiates a feedback cycle of inflammation, fibrosis, oxidative stress and cardiac mitochondrial damage via the PDE5A-cGMP-PKG pathway. Aim: To test if the PDE5A-cGMP-PKG pathway may contribute to burn-induced heart dysfunction. Methods: Sprague–Dawley rats were divided four groups: sham; sham/sildenafil; 24 h post burn (60% total body surface area scald burn, harvested at 24 h post burn); and 24 h post burn/sildenafil. We monitored heart function and oxidative adducts, as well as cardiac inflammatory, cardiac fibrosis and cardiac remodeling responses in vivo. Results: Sildenafil inhibited the burn-induced PDE5A mRNA level and increased the cGMP level and PKG activity, leading to the normalization of PKG down-regulated genes (IRAG, PLB, RGS2, RhoA and MYTP), a decreased ROS level (H2O2), decreased oxidatively modified adducts (malonyldialdehyde [MDA], carbonyls), attenuated fibrogenesis as well as fibrosis gene expression (ANP, BNP, COL1A2, COL3A2, αSMA and αsk-Actin), and reduced inflammation and related gene expression (RELA, IL-18 and TGF-β) after the burn. Additionally, sildenafil treatment preserved left ventricular heart function (CO, EF, SV, LVvol at systolic, LVPW at diastolic and FS) and recovered the oxidant/antioxidant balance (total antioxidant, total SOD activity and Cu,ZnSOD activity). Conclusions: The PDE5A-cGMP-PKG pathway mediates burn-induced heart dysfunction. Sildenafil treatment recovers burn-induced cardiac dysfunction.

Abstract 232: PDE5A Inhibition in Burn-induced Cardiac Dysfunction

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Jake J Wen ◽  
Ravi S Radhakrishnan
Keyword(s):  
Gene Expression ◽  
Burn Injury ◽  
Heart Function ◽  
Total Body Surface Area ◽  
Left Ventricular ◽  
Sod Activity ◽  
Heart Dysfunction ◽  
Translational Study ◽  
Total Antioxidant ◽  
Oxidatively Modified

Severe burn injury initiates a feedback cycle of inflammation, fibrosis and oxidative stress and others that may contribute to heart dysfunction via the PDE5A-cGMP-PKG pathway. Sildenafil (SIL) has been shown decrease immune adverse events in multiple cardiac diseases by inhibition of PDE5A. In this study, using Nano LC MS/MS strategy to identify differentially expressed proteins, we will determined the pathological importance of PDE5A-dependent injury in burn-related heart dysfunction using our well-established rat model with 4 groups: sham; sham/SIL (sham with sildenafil injection); 24 hpb (60% total body surface area scald burn and harvested at 24 hours post burn) and 24 hpb/SIL (24 hpb with SIL immediately after burn). We performed proteomics, Vevo 2100 ECG, qPCR, histology and ELISA to test our hypothesis. Our results show Sildenafil 1) inhibited burn-induced PDE5A mRNA, 2) increased cGMP and PKG activity leading to recover of PKG down-regulated genes (IRAG, PLB, RGS2, RhoA and MYTP), 3) decreased the ROS level (H2O2), oxidatively modified adducts (malonyldialdehyde (MDA), carbonyls), fibrotic gene expression (ANP, BNP, COL1A2, COL3A2, aSMA and αsk-Actin), inflammation-related gene expression (RELA, IL-18 and TGF-β) from burned rats (BRs) and 4) preserved Left-ventricular heart function (CO, EF, SV, LVvol at systolic, LVPW at diastolic and FS) and restored the oxidant/antioxidant balance (total antioxidant, total SOD activity and Cu,ZnSOD activity) in BRs. We demonstrate that the PDE5A-cGMP-PKG pathway mediates burn-induced heart dysfunction and will provide the theoretic foundation to guide pre-clinical translational study of Sildenafil in burned patients.

Abstract 12567: Circulating Factors Induce Cardiomyopathy After Burn Injury

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Jake J Wen ◽  
◽  
◽  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Burn Injury ◽  
Membrane Integrity ◽  
Bioactive Molecules ◽  
Cgmp Level ◽  
Heart Dysfunction ◽  
Atp Production ◽  
Human Cardiomyocytes ◽  
Upregulated Genes

Introduction: Our previous results in vivo indicated PDE5-cGMP-PKG was involved in burn-induced heart dysfunction and PDE5A inhibitor restored the dysfunction. It’s unknown if circulating factors after burn would injure cardiomyocytes. Hypothesis: Circulating factors released after burn induce cardiomyopathy. Methods: Human cardiomyocytes (AC16) were treated with sham-serum, burn-serum (24 hpb-serum) and burn/sildenafil-serum (24 hpb/SIL). We performed cut-edged biochemistry technologies and Illumina RNA sequencing (RNA-seq) in this study. GraphPad Prism 8.4.2 was used for statistics. Results: We found a significant decrease of cGMP level and an increase of cTN1 in 24 hpb-serum group. Treatment with the PDE5A inhibitor Sildenafil completely reversed this change similar to our in vivo work. To understand what bioactive molecules would be involved in the alterations by burn injury, human cardiomyocytes (Ac16) were employed to test the cardiomyocyte response to burn-induced circulating factors. We observed that 24 hpb-serum significantly 1) decreased cell viability and cell proliferation; as well as 2) increased cell cytotoxicity, cell apoptosis and cell ROS production. We also found 24 hpb-serum resulted in cell mitochondrial dysfunction by decreasing ATP production and mitochondrial membrane integrity/potential and increasing mitochondrial ROS. Seahorse and O2K approaches confirmed 24 hpb-serum-induced cardiomyocyte mitochondrial dysfunction as evidenced by decreases of mitochondrial basal respiration, proton leak, ATP production, and maximal respiration. 24 hpb/SIL serum rescued 24 hpb serum-induced Ac 16 cell response, at least partially. Advanced bioinformatic analyses identified 1415 upregulated genes and 1091 downregulated genes in 24 hpb-serum group and 776 upregulated genes and 113 downregulated genes restored in 24 hpb/SIL-serum group. We also analyzed and validated the differentially expressed genes. Conclusions: Our study not only confirmed burn induced heart dysfunction, but also provided evidence for understanding the pathogenic mechanism of circulating factors released after burn injury and preliminary genomic evidence for the mechanism for cardiomyopathy after burn injury.

scholarly journals A Porcine Model of Heart Failure With Preserved Ejection Fraction Induced by Chronic Pressure Overload Characterized by Cardiac Fibrosis and Remodeling

2021 ◽  
Vol 8 ◽  
Author(s):  
Weijiang Tan ◽  
Xiang Li ◽  
Shuang Zheng ◽  
Xiaohui Li ◽  
Xiaoshen Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Ejection Fraction ◽  
Cardiac Fibrosis ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Pathological Examination ◽  
Type I ◽  
Preserved Ejection Fraction

Heart failure is induced by multiple pathological mechanisms, and current therapies are ineffective against heart failure with preserved ejection fraction (HFpEF). As there are limited animal models of HFpEF, its underlying mechanisms have not yet been elucidated. Here, we employed the descending aortic constriction (DAC) technique to induce chronic pressure overload in the left ventricles of Tibetan minipigs for 12 weeks. Cardiac function, pathological and cellular changes, fibrotic signaling activation, and gene expression profiles were explored. The left ventricles developed concentric hypertrophy from weeks 4 to 6 and transition to dilation starting in week 10. Notably, the left ventricular ejection fraction was maintained at >50% in the DAC group during the 12-week period. Pathological examination, biochemical analyses, and gene profile analysis revealed evidence of inflammation, fibrosis, cell death, and myofilament dephosphorylation in the myocardium of HFpEF model animals, together with gene expression shifts promoting cardiac remodeling and downregulating metabolic pathways. Furthermore, we noted the activation of several signaling proteins that impact cardiac fibrosis and remodeling, including transforming growth factor-β/SMAD family members 2/3, type I/III/V collagens, phosphatidylinositol 3-kinase, extracellular signal-regulated kinase, matrix metalloproteinases 2 and 9, tissue inhibitor of metalloproteinases 1 and 2, interleukins 6 and 1β, and inhibitor of κBα/nuclear factor-κB. Our findings demonstrate that this chronic pressure overload-induced porcine HFpEF model is a powerful tool to elucidate the mechanisms of this disease and translate preclinical findings.

scholarly journals Involvement of Sirtuins and Klotho in Cardioprotective Effects of Exercise Training Against Waterpipe Tobacco Smoking-Induced Heart Dysfunction

2021 ◽  
Vol 12 ◽  
Author(s):  
Samaneh Sadat Alavi ◽  
Siyavash Joukar ◽  
Farzaneh Rostamzadeh ◽  
Hamid Najafipour ◽  
Fatemeh Darvishzadeh-mahani ◽  
...  
Keyword(s):  
Exercise Training ◽  
Tobacco Smoking ◽  
Diastolic Pressure ◽  
Heart Function ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Smoke Inhalation ◽  
Control Group ◽  
Heart Dysfunction ◽  
Waterpipe Tobacco Smoking

Despite its negative effect on the cardiovascular system, waterpipe smoking (WPS) is currently popular worldwide, especially among youth. This study investigated the effects of moderate endurance exercise on heart function of rats exposed to WPS and its possible mechanism. The animals were randomly divided into four groups: control group (CTL), the exercise group (Ex) which trained for 8 weeks, the waterpipe tobacco smoking group (S) exposed to smoke inhalation (30 min per day, 5 days each week, for 8 weeks), and the group that did exercise training and received waterpipe tobacco smoke inhalation together (Ex + S). One day after the last session of Ex and WPS, cardiac pressures and functional indices were recorded and calculated. The levels of SIRT1, SIRT3, Klotho, Bax, and Bcl-2 in the serum and heart, the expression of phosphorylated GSK3β of heart tissue, and cardiac histopathological changes were assessed. WPS reduced systolic pressure, +dP/dt max, -dP/dt max, and heart contractility indices (P < 0.001 vs. CTL) and increased cardiac tissue lesions (P < 0.05 vs. CTL) and end diastolic pressure and Tau index (P < 0.001 vs. CTL) of the left ventricle. Exercise training normalized the left ventricular end diastolic pressure, +dP/dt max, and contractility index. Also, exercise improved the levels of SIRT1, SIRT3, Klotho, and Bcl-2 and reduced Bax level in the heart. The findings showed that WPS causes left ventricular dysfunction. Moderate exercise prevented WPS-induced heart dysfunction partly through its anti-apoptotic features and activation of the sirtuins and Klotho pathways.

P1614Soluble guanylate cyclase as a therapeutic target in heart failure: myocardial gene expression in response to sGC stimulation in pressure overload

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
J Ruedebusch ◽  
A Benkner ◽  
N Nath ◽  
L Kaderali ◽  
K Klingel ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Expression Pattern ◽  
Heart Function ◽  
Gene Expression Pattern ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Marker Genes ◽  
Cgmp Pathway

Abstract Background Heart Failure (HF) is associated with endothelial dysfunction and reduced bioavailability of NO with insufficient stimulation of sGC and reduced production of cGMP. Therefore, the impairment of the NO-sGC-cGMP pathway results in vasoconstriction, platelet aggregation, inflammation, fibrosis and most importantly maladaptive cardiac hypertrophy. The restoration of the NO-sGC -cGMP pathway is an attractive pharmacological target for HF therapy. Purpose Riociguat is an NO independent stimulator of the sGC that sensitizes the sGC to endogenous NO and directly stimulates sGC to produce cGMP. We therefore hypothesized that Riociguat prevents pathological effects occurring during HF. Methods Pressure overload was induced by transverse aortic constriction (TAC) in 8 weeks old male C57Bl6/N mice. Three weeks after TAC when cardiac hypertrophy has developed either Riociguat (RIO; 3 mg/kg) or a Solvent was administered daily for 5 more weeks (n=12 per group). Animals with sham surgery and same drug regime served as controls. The heart function in all groups was evaluated weekly by small animal echocardiography. Eight weeks after surgery, the transcriptome of the left ventricles (LV) of sham and TAC mice were analysed by RNA Sequencing. Differentially expressed genes (DEG) were categorised using Ingenuity Pathway Analysis (IPA). Results TAC resulted in a steady decrease of left ventricular fractional shortening (FS) in the mice until week 3. When Riociguat treatment commenced, the systolic LV function of the TAC+Rio group recovered significantly whereas the solvent group showed a further decline until week 8 (FS 21.4±3.4% vs. 9.5±2%, p<0.001). Both sham groups (Sham+Sol and Sham+Rio) showed no changes in the heart function over timer. Regarding the hypertrophic response to LV pressure overload, Riociguat treatment attenuated significantly the increase of the left ventricular mass (LVM 208.3±15.8mg vs. 148.9±11.8mg, p<0.001) after TAC. In line with the reduced LVM, histological staining showed a significantly reduced fibrosis and myocyte cross sectional area in the TAC+Rio group compared to TAC+Sol group. Regarding the myocardial transcriptome, the treatment with Riociguat resulted in less changes of gene expression pattern after TAC (TAC+Sol vs. Sham+Sol 3160 DEG; TAC+Rio vs. Sham+Rio 2237 DEG). The expression of heart failure marker genes like ANP (Nppa), BNP (Nppb), β-Myosin Heavy Chain (Myh7) and the Collagens 1 and 3 (Col1a1, Col1a2, Col3a1) were significantly decreased in TAC+Rio, when compared to TAC+Sol. IPA analysis revealed that the activation of biological pathways in response to TAC, like actin cytoskeleton- and Integrin signalling, renin-angiotensin or cardiac hypertrophy signalling was attenuated when Riociguat was administered. Conclusion Riociguat attenuates pressure overload induced LV remodelling resulting in less hypertrophy, improved heart function and less alteration of gene expression pattern.

Is the Use of Routine Echocardiogram Warranted in Large Pediatric Burns?

2021 ◽  
Author(s):  
I Wilmot ◽  
P H Chang ◽  
L Fowler ◽  
P Warner
Keyword(s):  
Left Ventricular Dysfunction ◽  
Cardiac Dysfunction ◽  
Ventricular Dysfunction ◽  
Burn Injury ◽  
Early Recognition ◽  
Total Body Surface Area ◽  
Left Ventricular ◽  
Burn Patients ◽  
Severe Left Ventricular Dysfunction ◽  
Pediatric Burns

Abstract Introduction Cardiac dysfunction can develop in large pediatric burns during the acute and recovery phase. When occurring in this population, the cardiac abnormality appears as left ventricular dysfunction or dilated cardiomyopathy. Recent studies have demonstrated perioperative and long-term cardiac dysfunction resulting in longer hospital stays for patients over 40% total body surface area. The objective of this study was to assess if early use of echocardiograms in large burns would allow for early recognition of patients at risk for cardiac dysfunction. Material and Methods Pediatric burn patients ages 0-18 years who sustained a burn injury of 30% TBSA or more or developed cardiac dysfunction during hospital course were evaluated. Echocardiograms were obtained upon admission with monthly repeats until three normal studies were attained or the patient was discharged and when symptomatic. Results Of the 130 acute burn patients admitted during 7/2017-10/2018, 10 patients met criteria for enrollment in this study. The average age was 5 years (0.8 to 10 yrs), 70% were males and 90% sustained flame injuries.Total TBSA average was 45% (24-70%) with average full thickness burns of 33% (0-67%). Twenty echocardiogram studies were obtained. One patient with 25% TBSA burn, demonstrated severe left ventricular dysfunction with an EF of 25% from post arrest myocardial stunning. Repeat echocardiogram studies demonstrated full recovery with normal EF. The remaining patients, despite large TBSA injuries, did not exhibit any abnormalities on ECHO examinations. No cardiac interventions were required. Conclusions Use of echocardiograms is best performed on symptomatic burn patient populations.

Abstract P112: Decreased α-Myosin Expression is Associated with Left Ventricular Hypertrophy in Hypertensive Caribbean Vervets

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Chelsea C Weaver ◽  
Anthony Gutierrez ◽  
Jeffrey L Osborn
Keyword(s):  
Gene Expression ◽  
Left Ventricular Hypertrophy ◽  
Ventricular Hypertrophy ◽  
Cardiac Fibrosis ◽  
Peripheral Resistance ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Protein Isoforms ◽  
Left Ventricular Myocardium ◽  
Human Heart Failure

Caribbean vervets ( Chlorocebus aethiops sabeus ) develop hypertension (HT; Systolic Blood Pressure ≥ 140 mmHg) in over 30% (125/345) of the outbred population. Elevated total peripheral resistance in HT increases cardiac afterload, which may lead to left ventricular hypertrophy (LVH) and cardiac remodeling. We hypothesize that prolonged spontaneous HT is associated with LVH, cardiac and aortic fibrosis, as well as differential transcription of myocardial contractile proteins. Vervets were characterized as HT (SBP = 170 ± 25.3 mmHg; n=125) or normotensive (NT, SBP = 99 ± 14.5 mmHg; n=148) using forearm plethysmography (ketamine sedated;15 mg/kg i.m.). Cardiomyocyte cross-sectional area was greater in HT compared to NT animals (HT 283 ± 52 μm 2 , n=9 vs NT 114 ± 8 μm 2 , n=10; p<0.01). Average collagen stained as a function of tissue area was similar in left ventricular myocardium of HT and NT animals (HT 14.17 ± 3.13% or 0.17/1.21 mm 2 , n=9 vs NT 12.22 ± 0.80% or 0.16/1.27 mm 2 , n=10; p>0.05). Aortic adventia collagen area was greater in HT compared to NT vervets (HT 66.12 ± 4.22% or 0.60/0.90 mm 2 , n=6 vs NT 54.53 ± 2.21% or 0.56/1.02 mm 2 , n=10; p<0.05). Total tissue collagen was estimated using a hydroxyproline assay. Collagen content was not different between HT and NT vervets for left ventricular myocardium (HT 194.02 ± 8.61 μg/mL, n=11 vs NT 201.70 ± 18.89 μg/mL, n=10; p=0.71) or aorta (HT 745.64 ± 44.49 μg/mL, n=11 vs NT 668.39 ± 31.06 μg/mL, n=11; p=0.17). Myosin gene expression (α and β) was estimated using RT-PCR of mRNA in left ventricular myocardium of NT (SBP = 98.91 ±10.89 mmHg; n=20) and HT (SBP = 171.51 ± 30.28 mmHg; n=17) vervets. α-myosin was downregulated in HT compared to NT vervets (HT RQ = 0.10 ± 0.03 vs. NT RQ = 0.22 ± 0.04; p<0.05), while β-myosin expression was not different (HT RQ = 0.22 ± 0.17 vs. NT RQ = 0.20 ± 0.16; p=0.83). Thus, spontaneous HT in outbred vervets induces LVH in response to factors other than cardiac fibrosis. Myosin gene expression may shift from α-myosin to other contractile protein isoforms, characteristic of human heart failure. In this nonhuman primate model, HT does not induce significant aortic fibrosis that may occur in aged animals. Future studies will further characterize contractile and pro-inflammatory proteins in LVH of spontaneous HT vervets.

scholarly journals Blockade of KCa3.1 Attenuates Left Ventricular Remodeling after Experimental Myocardial Infarction

2015 ◽  
Vol 36 (4) ◽  
pp. 1305-1315 ◽  
Author(s):  
Chen-Hui Ju ◽  
Xian-Pei Wang ◽  
Chuan-Yu Gao ◽  
Shuang-Xia Zhang ◽  
Xing-Hua Ma ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Fibrosis ◽  
Ventricular Remodeling ◽  
Heart Function ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Experimental Myocardial Infarction ◽  
Ang Ii ◽  
Pharmacological Blockade

Background/Aims: After myocardial infarction (MI), cardiac fibrosis greatly contributes to left ventricular remodeling and heart failure. The intermediate-conductance calcium-activated potassium Channel (KCa3.1) has been recently proposed as an attractive target of fibrosis. The present study aimed to detect the effects of KCa3.1 blockade on ventricular remodeling following MI and its potential mechanisms. Methods: Myocardial expression of KCa3.1 was initially measured in a mouse MI model by Western blot and real time-polymerase chain reaction. Then after treatment with TRAM-34, a highly selective KCa3.1 blocker, heart function and fibrosis were evaluated by echocardiography, histology and immunohistochemistry. Furthermore, the role of KCa3.1 in neonatal mouse cardiac fibroblasts (CFs) stimulated by angiotensin II (Ang II) was tested. Results: Myocardium expressed high level of KCa3.1 after MI. Pharmacological blockade of KCa3.1 channel improved heart function and reduced ventricular dilation and fibrosis. Besides, a lower prevalence of myofibroblasts was found in TRAM-34 treatment group. In vitro studies KCa3.1 was up regulated in CFs induced by Ang II and suppressed by its blocker.KCa3.1 pharmacological blockade attenuated CFs proliferation, differentiation and profibrogenic genes expression and may regulating through AKT and ERK1/2 pathways. Conclusion: Blockade of KCa3.1 is able to attenuate ventricular remodeling after MI through inhibiting the pro-fibrotic effects of CFs.

Abstract 169: Angiotensin-II Induced Left Ventricular Remodeling Differs Between C57bl/6 Substrains

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Sophie Cardin ◽  
Marie-Pier Scott-Boyer ◽  
Sylvie Picard ◽  
Tim L Reudelhuber ◽  
Christian F Deschepper
Keyword(s):  
Gene Expression ◽  
Angiotensin Ii ◽  
Cardiac Fibrosis ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Cardiovascular Research ◽  
Lv Remodeling ◽  
Fold Induction ◽  
Subsequent Activation

Background: Although C57Bl/6 mice are widely used in cardiovascular research, little is known about possible substrain differences. We compared the left ventricular (LV) remodeling induced by angiotensin II (angII) in C57Bl/6J and C57Bl/6N mice, these 2 substrains corresponding to two main branches having diverged since 1951. Methods and Results: Male C57Bl/6J and C57Bl/6N mice were treated with angII (350ng/kg/min) or vehicle via mini-osmotic pumps for either 48h (for microarray profiling of gene expression and macrophage cytofluorometry counting) or 15 days (for both gene expression and histology). AngII (15d) induced fibrosis in LV from C57BL/6N (as shown by histology and col1a expression), but not in C57BL/6J. After 48h of treatment, about 100 genes responded in a strain-specific fashion, most responses being specific for C57Bl/6N mice. Among genes showing greater than 2-fold induction by angII (48h) in C57Bl/6N mice, there was enrichment for markers of macrophages activation and M2 polarization (including osteopontin, arginase1 and galectin3). These strain-specific differences were confirmed (both in LV tissues and macrophages isolated from LVs) by Q-RT-PCR, and occurred despite that fact that AngII increased the abundance of Cd11b+ macrophages to the same extent in both strains. Moreover, AngII (48h) increased expression of several markers of fibroblast activation (including Timp1, Lox and tenascin) in C57Bl/6N (both in LV tissue and fibroblasts isolated from LVs), but not in C57Bl/6J. Although one of the best known genetic differences in both substrains is the inactivation of the Nnt gene in C57Bl6/J mice, experiments performed in F2 mice do not indicate that the fibrotic response co-segregates with the Nnt mutation. Conclusions: Although angII-treatment induces macrophage recruitment in the LVs of both C57Bl/6J and C57Bl/6N mice, activation of cardiac macrophages and their M2 pro-reparative polarization (with subsequent activation of fibroblasts and synthesis of collagen) occurs only in the genetic C57Bl/6N background. The absence of macrophage activation and cardiac fibrosis in C57BL/6J may possibly explain some differences in experimental results obtained by various investigators using different C57BL/6 substrains.

Abstract 162: Cardiac Overexpression of Senescence Marker Protein 30 Inhibits Angiotensin II-Induced Cardiac Hypertrophy and Remodeling

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Tomofumi Misaka ◽  
Satoshi Suzuki ◽  
Makiko Miyata ◽  
Atsushi Kobayashi ◽  
Shu-ichi Saitoh ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Mrna Level ◽  
Protective Role ◽  
Left Ventricular ◽  
Heart Weight ◽  
Ang Ii ◽  
Marker Protein ◽  
Aging Effects

Backgrounds: Senescence marker protein 30 (SMP30) was originally identified as an important aging marker protein, and assumed to behave as an anti-aging factor. Previously, we demonstrated that deficiency of SMP30 exacerbates angiotensin II (Ang II)-induced reactive oxygen species (ROS) and cardiac adverse remodeling, suggesting that SMP30 may have a protective role in the heart. Thus, this study aimed to test the hypothesis that up-regulation of SMP30 inhibits cardiac hypertrophy and remodeling in response to Ang II. Methods: We generated transgenic (SMP30-TG) mice with cardiac-specific overexpression of SMP30 gene using α-myosin heavy chain promoter. SMP30-TG mice and wild type littermate (WT) were subjected to continuous Ang II infusion (800 ng/kg/min). Results: After 2 weeks, heart weight was significantly lower in SMP30-TG mice than in WT mice (P<0.01). Echocardiography revealed that calculated left ventricular mass and E/e’ were lower in SMP30-TG mice than in WT mice (P<0.01 and P<0.05, respectively), suggesting that diastolic function was preserved in SMP30-TG mice. Histological analysis showed that the degree of cardiac fibrosis was significantly decreased in SMP30-TG mice than in WT mice (P<0.05). Dihydroethidium staining demonstrated that generation of ROS was reduced in SMP30-TG mice compared with WT mice (P<0.05). Furthermore, the numbers of senescence-associated β-galactosidase-positive cardiomyocytes were decreased in SMP30-TG mice compared to WT mice (P<0.05). In addition, p21 mRNA level was significantly suppressed in SMP30-TG mice compared to WT mice (P<0.01). Conclusions: This study demonstrated cardiac-specific overexpression of SMP30 inhibits Ang II-induced cardiac hypertrophy and remodeling. These findings suggested that SMP30 has a cardio-protective role with anti-oxidative and anti-aging effects. Up-regulation of SMP30 might be a new strategy to approach senescent cardiac diseases and attenuate the development of heart failure particularly with hypertension.

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