Allylmethylsulfide, a Sulfur Compound Derived from Garlic, Attenuates Isoproterenol-Induced Cardiac Hypertrophy in Rats

Allylmethylsulfide (AMS) is a novel sulfur metabolite found in the garlic-fed serum of humans and animals. In the present study, we have observed that AMS is safe on chronic administration and has a potential antihypertrophic effect. Chronic administration of AMS for 30 days did not cause any significant differences in the body weight, electrocardiogram, food intake, serum biochemical parameters, and histopathology of vital organs. Single-dose pharmacokinetics of AMS suggests that AMS is rapidly metabolized into Allylmethylsulfoxide (AMSO) and Allylmethylsulfone (AMSO2). To evaluate the efficacy of AMS, cardiac hypertrophy was induced by subcutaneous implantation of ALZET® osmotic minipump containing isoproterenol (~5 mg/kg/day), cotreated with AMS (25 and 50 mg/kg/day) and enalapril (10 mg/kg/day) for 2 weeks. AMS and enalapril significantly reduced cardiac hypertrophy as studied by the heart weight to body weight ratio and mRNA expression of fetal genes (ANP and β-MHC). We have observed that TBARS, a parameter of lipid peroxidation, was reduced and the antioxidant enzymes (glutathione, catalase, and superoxide dismutase) were improved in the AMS and enalapril-cotreated hypertrophic hearts. The extracellular matrix (ECM) components such as matrix metalloproteinases (MMP2 and MMP9) were significantly upregulated in the diseased hearts; however, with the AMS and enalapril, it was preserved. Similarly, caspases 3, 7, and 9 were upregulated in hypertrophic hearts, and with the AMS and enalapril treatment, they were reduced. Further to corroborate this finding with in vitro data, we have checked the nuclear expression of caspase 3/7 in the H9c2 cells treated with isoproterenol and observed that AMS cotreatment reduced it significantly. Histopathological investigation of myocardium suggests AMS and enalapril treatment reduced fibrosis in hypertrophied hearts. Based on our experimental results, we conclude that AMS, an active metabolite of garlic, could reduce isoproterenol-induced cardiac hypertrophy by reducing oxidative stress, apoptosis, and stabilizing ECM components.

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Hypertension and Cardiac Hypertrophy in Growth Hormone-Deficient Rats

Clinical Science ◽

10.1042/cs0870239 ◽

1994 ◽

Vol 87 (2) ◽

pp. 239-243 ◽

Cited By ~ 5

Author(s):

Stephen B. Harrap ◽

Shari R. Datodi ◽

Emma K. Crapper ◽

Leon A. Bach

Keyword(s):

Blood Pressure ◽

Growth Hormone ◽

Body Weight ◽

Cardiac Hypertrophy ◽

Weight Ratio ◽

The Body ◽

Hormone Deficiency ◽

Heart Weight ◽

Deoxycorticosterone Acetate ◽

F344 Rats

1. Growth hormone may influence cardiac growth during post-natal maturation or in response to hypertension, and the growth-hormone deficient dwarf rat model offers an opportunity to study this question. 2. We compared the blood pressure and heart weight of dwarf rats and Fischer (F344) control rats in early adulthood, after two hypertensive stimuli: unilateral renal ischaemia (two-kidney, one-clip) or the administration of deoxycorticosterone acetate and saline drinking fluid. 3. In untreated animals at 13 weeks of age the body weight of dwarf rats was significantly less than that of F344 rats, but the mean arterial pressure was similar. Although the hearts of dwarf rats were smaller than those of F344 rats, the heart weight/body weight ratio was significantly greater in dwarf rats. 4. Both dwarf and F344 rats developed similar hypertensive mean arterial pressures 5 weeks after left renal artery clipping or treatment with deoxycorticosterone acetate salt. The heart weights of hypertensive dwarf and F344 rats were equivalent, indicating a proportionally greater increase in cardiac size in dwarf rats for the same rise in blood pressure. 5. The plasma insulin-like growth factor-I level was markedly lower in dwarf than in F344 rats, and hypertension did not have any significant effects on these levels. 6. These findings indicate that the developmental increase in blood pressure and heart size in growing animals and the adaptive cardiac hypertrophy accompanying hypertension are not affected by growth hormone deficiency.

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PO-148 Effect of Aerobic Exercise on the Expression of CaMKIIδ/MEF2 in Hypertensive and Physiological Cardiac Hypertrophy

Exercise Biochemistry Review ◽

10.14428/ebr.v1i4.10513 ◽

2018 ◽

Vol 1 (4) ◽

Author(s):

Man Zhu ◽

Lijun Shi

Keyword(s):

Body Weight ◽

Cardiac Hypertrophy ◽

Aerobic Exercise ◽

Weight Ratio ◽

Exercise Group ◽

The Body ◽

Expression Level ◽

Heart Weight ◽

Control Group ◽

Body Weight Ratio

Objective The type II calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδ) signal plays a key role in the development of cardiac hypertrophy. This study used CaMKIIδ as an entry point to investigate the mechanism of moderate-intensity aerobic exercise affecting myocardial function. Methods Male spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats (WKYs), 12 weeks age, were randomly divided into aerobic exercise group (SHR-EX/WKY-EX) and sedentary control group (SHR-SED/WKY-SED), with 12 rats in each group. The aerobic exercise group conducted an 8-week treadmill exercise training with a slope of 0°, 20m/min (about 55-65% of maximal aerobic velocity), 60min/day, and 5d/wk. The control group did not exercise. The body weight of each group of rats was measured weekly and the blood pressure of the rats was measured non-invasively. After 8 weeks, the hearts of SHR-EX group, WKY-EX group, SHR-SED group and WKY-SED group were weighed, and then myocardial tissue sections were taken for HE staining to observe the thickness of the ventricular wall and the morphology of myocardial cells. The expression of CaMKIIδ and MEF2 in each group was determined by Western blotting. Results (1) The body weight of SHR-SED group was significantly higher than that of SHR-EX group (p<0.01), and the heart weight of rats in exercise group changed significantly. The WKY-EX group had greater heart weight than the WKY-SED group, and the SHR-SED group was heavier than the SHR-EX group (p<0.05). The heart weight/body weight ratio of the WKY-EX group was significantly higher than that of the WKY-SED group (p<0.01). The heart weight/body weight ratio of SHR-EX group and SHR-SED group was higher than that of WKY-EX group and WKY-SED group (p<0.01). (2) Compared with the WKY-SED group, the SHR-SED group had loose interstitial cells and increased single cell area. The SHR-EX group is more compact than the SHR-SED group, and the cell cross-sectional area is reduced. (3) The expression of CaMKIIδ protein in SHR-EX group was significantly lower than that in SHR-SED group (p<0.01), but the expression level of CaMKIIδ in WKY-EX group was significantly higher than that in WKY-SED group (p<0.01). The expression level of CaMKIIδ was significantly higher in the SHR-SED group than in the WKY-SED group. In addition, the expression of MEF2 protein in SHR-EX group and WKY-SED group was significantly lower than that in SHR-SED group (p<0.01), while the MEF2 expression level in WKY-EX group was higher than WKY-SED group and SHR-EX group (p<0.05). Conclusions There is an interaction between aerobic exercise and hypertension. Aerobic exercise can effectively delay the development of hypertensive cardiac hypertrophy by regulating the expression of CaMKIIδ and MEF2 protein in the myocardium, but it can also cause cardiac hypertrophy in normal heart. It is one of the important mechanisms affecting the myocardial morphology and function.

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Abstract 670: Immediate And Sustained Blood Pressure Lowering by CRF-receptor Stimulation: A Novel Approach To Antihypertensive Therapy?

Circulation ◽

10.1161/circ.116.suppl_16.ii_124-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Thomas Dieterle ◽

Silvia Meili-Butz ◽

Katrin Buehler ◽

Christian Morandi ◽

Dietlinde John ◽

...

Keyword(s):

Blood Pressure ◽

Body Weight ◽

Arterial Hypertension ◽

Weight Ratio ◽

Chronic Administration ◽

Cardiovascular Responses ◽

High Salt ◽

Heart Weight ◽

Receptor Stimulation ◽

Novel Approach

Background: Recently, novel corticotropin-releasing factor (CRF)-related peptides, named urocortin I (UcnI), UcnII, and UcnIII were described. Available data suggest that the Ucns are part of a peripheral CRF system modulating cardiovascular function and mediating cardiovascular responses to stress. Blood pressure (BP) lowering effects have been described after administration of UcnI. However, no data are available on effects of UcnII on BP in an animal model of systemic arterial hypertension. Methods: Experiments were performed in Dahl salt-sensitive (DSS) and salt-resistant rats (DSR, control). Animals were fed a diet containing 4% NaCl (high salt) to induce arterial hypertension in DSS rats. At the end of week 2 of high salt diet, both DSS and DSR rats were randomly assigned to i.p. injections of either UcnII (2.5 μg/kg body weight) or vehicle b.i.d. for five weeks. Animals underwent repetitive tail cuff BP measurements at baseline (prior to first injection), at 5 and 15 minutes after the first injection and at week 1, 2, and 5 of b.i.d. treatment. At week 5 animals were sacrificed to determine heart weight /body weight ratio. Results: Systolic BP (SBP, mmHg) and heart rate (HR, min −1 ) are given in the following table as mean ± SD (n=10 per group). Conclusions: In hypertensive DSS rats, acute CRF-receptor stimulation by UcnII immediately lowered BP to the range observed in DSR rats. Compared to vehicle-treated DSS rats, sustained BP reduction was observed with further chronic administration of UcnII. No severe reflex tachycardia was observed after administration of UcnII. Thus, CRF-receptor stimulation might represent a novel approach to the treatment of arterial hypertension.

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Prostaglandin F2 alpha induces cardiac myocyte hypertrophy in vitro and cardiac growth in vivo

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1996.271.6.h2197 ◽

1996 ◽

Vol 271 (6) ◽

pp. H2197-H2208 ◽

Cited By ~ 12

Author(s):

J. Lai ◽

H. Jin ◽

R. Yang ◽

J. Winer ◽

W. Li ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Cardiac Myocyte ◽

Ventricular Myocytes ◽

Chronic Administration ◽

Heart Weight ◽

Adult Rats ◽

Myocyte Hypertrophy ◽

Cardiac Myocyte Hypertrophy

Several prostaglandins [prostaglandin (PG) A2, -B2, -D2, -E2, -F2 alpha, and -I2 and carbaprostacyclin] and the thromboxane analogue U-46619 were analyzed for the ability to induce hypertrophy of rat neonatal cardiac ventricular myocytes. Myocyte hypertrophy was induced specifically by PGF2 alpha. Myocytes exposed to this prostanoid in culture increased in size and protein content. The contractile fibrils within the cells became organized into parallel arrays, and the cells tended to cluster and beat spontaneously. PGF2 alpha also induced the expression of c-fos, atrial natriuretic factor (ANF), and alpha-skeletal actin in these cells. The effects of PGF2 alpha were compared with several known cardiac myocyte hypertrophy factors (phenylephrine, endothelin-1, leukemia inhibitory factor, cardiotrophin-1, and angiotensin II). PGF2 alpha was found to be intermediate in potency among the factors but induced a level of ANF production that was approximately 10-fold higher than any of the other effectors. Responsiveness to PGF2 alpha was not limited to neonatal cardiocytes. Ventricular myocytes isolated from adult rats also responded specifically to PGF2 alpha with a morphological change similar to that observed with phenylephrine and by producing ANF. In rats, chronic administration of fluprostenol, a potent agonist analogue of PGF2 alpha, resulted in a dose-dependent increase in heart weight- and ventricular weight-to-body weight ratios. The amount of PGF2 alpha extractable from the hearts of rats with cardiac hypertrophy induced by myocardial infarction was also found to be greater than that in sham-operated control rats. These results indicate that PGF2 alpha may play an important role in inducing cardiac hypertrophy.

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Studies of Body Weight/Heart Weight [C/S] Ratio in Treated and Untreated Experimental Pulmonary Barotrauma

Polish Hyperbaric Research ◽

10.2478/phr-2019-0020 ◽

2019 ◽

Vol 69 (4) ◽

pp. 63-70

Author(s):

Piotr Siermontowski ◽

Wojciech Kozłowski ◽

Katarzyna Pleskacz

Keyword(s):

Body Weight ◽

Weight Ratio ◽

Total Body Weight ◽

External Pressure ◽

The Body ◽

Heart Weight ◽

Control Group ◽

Pulmonary Barotrauma ◽

Pulmonary Parenchyma ◽

Sudden Decrease

AbstractThe prerequisite of development of pulmonary barotrauma [PB] is retention of the breathing mix in the lungs during a sudden decrease in external pressure or its administration into the airways under increased pressure or in a volume exceeding the maximum lung capacity. In such cases, the pulmonary parenchyma ruptures and air enters both the pleural cavity and/or the lumen of ruptured blood vessels located in the alveolar septa. The result is permanent disruption of the pulmonary parenchyma.The aim of the study was to assess the influence of post-PB lesions on the heart muscle and the importance of hyperbaric treatment on the exacerbation of such lesions in the heart. The hearts of 35 rabbits were used in the study. In animals of the experimental group, PB was induced in the pressure chamber using the proprietary method described in previous publications. Part of the animals in this group were treated with air hyperbaria. The comparison group consisted of animals, which did not undergo PB during a simulated dive. All animals were weighed, observed for four weeks and then put to death following the experiment. In autopsy, among others, whole hearts were collected and weighed after fixation. Subsequently, the C/S ratio, i.e. the body to heart weight ratio, was calculated. The measurement results were subject to statistical analysis. A statistically significant increase in the C/S ratio was found, indicating an increase in the share of heart weight in the total body weight in the group of animals with PB not treated with air hyperbaria as compared to the control group.

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Abstract 20118: Defining the Sufficiency of Atg7 to Suppress Phenylephrine-induced Cardiac Hypertrophy

Circulation ◽

10.1161/circ.130.suppl_2.20118 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Marcus Tjeerdsma ◽

Levi Froke ◽

Jessica Freeling ◽

Scott Pattison

Keyword(s):

Body Weight ◽

Cardiac Hypertrophy ◽

Cardiac Function ◽

Heart Weight ◽

Autophagic Flux ◽

Specific Expression ◽

Hypertrophic Growth ◽

Fractional Shortening

Introduction: Macroautophagy is a process of bulk protein degradation. Our prior work showed that Atg7 expression is sufficient to induce autophagic flux in vitro and in vivo . When Atg7 was co-expressed with CryAB R120G in the heart, cardiac hypertrophy was blunted in heart weight/body weight ratios and fetal gene expression markers. To determine if Atg7 expression is sufficient to limit hypertrophic growth in another model, we tested the effects of Atg7 overexpression with phenylephrine-induced hypertrophy both in vitro and in vivo . Hypothesis: Atg7 will blunt the hypertrophic effects of phenylephrine. Methods: Rat neonatal cardiomyocytes were infected with adenoviruses expressing either LacZ or Atg7 and treated with phenylephrine to induce cardiomyocytes hypertrophy. Osmotic pumps were surgically implanted into control mice and mice with cardiac-specific expression of Atg7 to infuse phenylephrine (PE) or vehicle (saline) for four weeks. Results: PE treatment significantly increased neonatal cardiomyocyte areas in LacZ-expressing cells, while Atg7-expressing cardiomyocytes showed no growth. In mice, all genotypes responded to PE treatment with significantly increased heart weight/body weight ratios and increased fiber size. However, Atg7-expressing hearts differed significantly from control hearts in normalized heart mass following PE delivery. Vehicle treated Atg7-expressing hearts had 17% smaller myofiber cross-sectional areas than those from control genotypes and had a reduced hypertrophic response to PE, relative to controls. Echocardiography showed that Atg7-expressing hearts had significantly elevated cardiac function (% fractional shortening) prior to and throughout the experiment over control hearts (33% vs. 29%). PE significantly increased fractional shortening) from 29% to 36% in control hearts, but failed to significantly elevate cardiac function in Atg7-expressing hearts further (33% vs 35%). Additional assays are underway to understand the Atg7-dependent adaptations to PE. Conclusion: Atg7 expression yields modestly smaller hearts with enhanced cardiac function which may protect them from hypertrophic stresses like phenylephrine.

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Abstract P141: Cardiac TRH Partly Mediates Angiotensin II-induced Fibrotic and Hypertrophy Effects in "in vivo" and "in vitro" Models

Hypertension ◽

10.1161/hyp.66.suppl_1.p141 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Silvia I García ◽

Ludmila S Peres Diaz ◽

Maia Aisicovich ◽

Mariano L Schuman ◽

María S Landa

Keyword(s):

Gene Expression ◽

Body Weight ◽

Cardiac Hypertrophy ◽

Structural Changes ◽

In Vitro Models ◽

Heart Weight ◽

Saline Control ◽

Control Group

Cardiac TRH (cTRH) is overexpressed in the hypertrophied ventricle (LV) of the SHR. Additionally in vivo siRNA-TRH treatment induced downregulation of LV-TRH preventing cardiac hypertrophy and fibrosis demonstrating that TRH is involved in hypertrophic and fibrotic processes. Moreover, in a normal heart, the increase of LV TRH expression alone could induce structural changes where fibrosis and hypertrophy could be involved, independently of any other system alterations. Is well-known the cardiac hypertrophy/ fibrotic effects induced by AII, raising the question of whether specific LV cTRH inhibition might attenuates AII induced cardiac hypertrophy and fibrosis in mice. We challenged C57 mice with AII (osmotic pumps,14 days; 2 mg/kg) to induce cardiac hypertrophy vs saline. Groups were divided and , simultaneously to pump surgery, injected intracardiac with siRNA-TRH and siRNA-Con as its control. Body weight, water consume and SABP were measured daily. As expected, AII significantly increased SABP (p<0.05) in both groups treated , although cardiac hypertrophy (heart weight/body weight) was only evident in the group with the cardiac TRH system undamaged, suggesting that the cardiac TRH system function as a necessary mediator of the AII-induced hypertrophic effect. As hypothesized, we found an AII-induced increase of TRH (p<0.05) gene expression (real-t PCR) confirmed by immunofluorescence that was not observed in the group AII+siRNA-TRH demonstrating the specific siRNA treatment efficiency. Furthermore, AII significantly increase (p<0.05) BNP (hypertrophic marker), III collagen and TGFB (fibrosis markers) expressions only in the group with AII with the cardiac TRH system intact. On the contrary, the group with AII and the cTRH system inhibited, shows genes expressions similar to the saline control group. We confirmed these results by immunofluorescence. Similar fibrotic results were observed with NIH3T3 cell culture where we demonstrated that AII induced TRH gene expression (p<0.05) and its inhibition impedes AII-induced increase of TGFB and III/I collagens expressions telling us about the role of the cTRH in the AII fibrosis effects. Our results point out that the cardiac TRH is involved in the AII-induced hypertrophic and fibrotic effects.

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Genistein prevents isoproterenol-induced cardiac hypertrophy in rats

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y2012-068 ◽

2012 ◽

Vol 90 (8) ◽

pp. 1117-1125 ◽

Cited By ~ 21

Author(s):

Subir Kumar Maulik ◽

Pankaj Prabhakar ◽

Amit Kumar Dinda ◽

Sandeep Seth

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Body Weight ◽

Nitric Oxide Synthase ◽

Cardiac Hypertrophy ◽

Weight Ratio ◽

Left Ventricular ◽

Heart Weight ◽

Once Daily ◽

Oxide Synthase

Genistein, an isoflavone and a rich constituent of soy, possesses important regulatory effects on nitric oxide (NO) synthesis and oxidative stress. Transient and low release of NO by endothelial nitric oxide synthase (eNOS) has been shown to be beneficial, while high and sustained release by inducible nitric oxide synthase (iNOS) may be detrimental in pathological cardiac hypertrophy. The present study was designed to evaluate whether genistein could prevent isoproterenol-induced cardiac hypertrophy in male Wistar rats (150–200 g, 10–12 weeks old) rats. Isoproterenol (5 mg·(kg body weight)–1) was injected subcutaneously once daily for 14 days to induced cardiac hypertrophy. Genistein (0.1 and 0.2 mg·kg–1, subcutaneous injection once daily) was administered along with isoproterenol. Heart tissue was studied for myocyte size and fibrosis. Myocardial thiobarbituric acid reactive substances (TBARS), glutathione (GSH), superoxide dismutase (SOD), catalase levels, and 1-OH proline (collagen content) were also estimated. Genistein significantly prevented any isoproterenol-induced increase in heart weight to body weight ratio, left ventricular mass (echocardiographic), myocardial 1-OH proline, fibrosis, myocyte size and myocardial oxidative stress. These beneficial effects of genistein were blocked by a nonselective NOS inhibitor (L-NAME), but not by a selective iNOS inhibitor (aminoguanidine). Thus, the present study suggests that the salutary effects of genistein on isoproterenol-induced cardiac hypertrophy may be mediated through inhibition of iNOS and potentiation of eNOS activities.

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Bawei Chenxiang Wan Ameliorates Cardiac Hypertrophy by Activating AMPK/PPAR-α Signaling Pathway Improving Energy Metabolism

Frontiers in Pharmacology ◽

10.3389/fphar.2021.653901 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiaoying Zhang ◽

Zhiying Zhang ◽

Pengxiang Wang ◽

Yiwei Han ◽

Lijun Liu ◽

...

Keyword(s):

Body Weight ◽

Energy Metabolism ◽

Cardiac Hypertrophy ◽

Heart Function ◽

Weight Ratio ◽

Tibetan Medicine ◽

Heart Weight ◽

Cardiomyocyte Hypertrophy ◽

Body Weight Ratio ◽

Cross Sectional

Bawei Chenxiang Wan (BCW), a well-known traditional Chinese Tibetan medicine formula, is effective for the treatment of acute and chronic cardiovascular diseases. In the present study, we investigated the effect of BCW in cardiac hypertrophy and underlying mechanisms. The dose of 0.2, 0.4, and 0.8 g/kg BCW treated cardiac hypertrophy in SD rat model induced by isoprenaline (ISO). Our results showed that BCW (0.4 g/kg) could repress cardiac hypertrophy, indicated by macro morphology, heart weight to body weight ratio (HW/BW), left ventricle heart weight to body weight ratio (LVW/BW), hypertrophy markers, heart function, pathological structure, cross-sectional area (CSA) of myocardial cells, and the myocardial enzymes. Furthermore, we declared the mechanism of BCW anti-hypertrophy effect was associated with activating adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/peroxisome proliferator–activated receptor-α (PPAR-α) signals, which regulate carnitine palmitoyltransferase1β (CPT-1β) and glucose transport-4 (GLUT-4) to ameliorate glycolipid metabolism. Moreover, BCW also elevated mitochondrial DNA-encoded genes of NADH dehydrogenase subunit 1(ND1), cytochrome b (Cytb), and mitochondrially encoded cytochrome coxidase I (mt-co1) expression, which was associated with mitochondria function and oxidative phosphorylation. Subsequently, knocking down AMPK by siRNA significantly can reverse the anti-hypertrophy effect of BCW indicated by hypertrophy markers and cell surface of cardiomyocytes. In conclusion, BCW prevents ISO-induced cardiomyocyte hypertrophy by activating AMPK/PPAR-α to alleviate the disturbance in energy metabolism. Therefore, BCW can be used as an alternative drug for the treatment of cardiac hypertrophy.

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Abstract 385: Tenascin-C Worsens Myocardial Inflammation and Fibrosis by Enhancing Macrophage Activation via NF-kappaB in Mouse Hypertensive Heart

Hypertension ◽

10.1161/hyp.62.suppl_1.a385 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Naoshi Shimojo ◽

Ryotaro Hashizume ◽

Mari Hara ◽

Yuka Suzuki ◽

Tomohiro Nishioka ◽

...

Keyword(s):

Body Weight ◽

Macrophage Activation ◽

Weight Ratio ◽

Integrin Αvβ3 ◽

Heart Weight ◽

Pcr Analysis ◽

Dependent Manner ◽

Tenascin C ◽

Nf Kappab

Background and Aim: Tenascin-C (TN-C) is an extracellular matrix glycoprotein, not detected in normal adult heart but it expresses under various pathological conditions. We have previously reported in the enhanced TN-C production and accumulation of macrophages in the perivascular lesions of angiotensin II (AgII)-induced cardiac fibrosis mouse model. To clarify the role of TN-C in molecular mechanism, we analyzed the effect of TN-C in hypertensive heart utilizing wild-type (WT) and TN-C knock-out (TNKO) mice. Furthermore, to assess whether TN-C is involved in macrophage activation, we investigated in vitro study using macrophages isolated from the peritoneal cavity of WT mice. Methods and Results: Balb/c WT and TNKO mice were treated with 560 ng/kg body weight/min AgII subcutaneously by osmotic minipump for 4 weeks (WT/AgII and TNKO/AgII), and analyzed histological and molecular biological approaches. AgII treatment increased blood pressure, heart weight/body weight ratio, atrial and brain natriuretic peptide expression level and sizes of cardiomyocytes, but no significant differences were detected between WT/AgII and TNKO/AgII mice. In WT/AgII mice, interstitial collagen fibers (10.29±5.09% vs. WT: 4.6±1.56%, p<0.001) and accumulation of mac-3 positive macrophages (50±15.13 vs. WT: 6±2.55 cells/section, p<0.001) were observed at perivascular regions, and expression levels of interleukin (IL)-6 (1.85±0.39 fold, p<0.05) and monocyte chemoattractant protein (MCP)-1 (3.20±0.53 fold, p<0.001) were up-regulated. These changes were significantly reduced in TNKO/AgII mice. In vitro, TN-C accelerated macrophage migration in the presence of MCP-1. Western blotting and Immunofluorescence staining indicated that TN-C activated rapidly NF-kappaB. RT-PCR analysis demonstrated that TN-C up-regulated IL-6 mRNA on NF-kappaB dependent manner (39.90±18.10 fold, p<0.01). Integrin αVβ3 antagonist P11 suppressed these changes. Conclusion: The present study clearly demonstrated that TN-C aggravates inflammation and fibrosis in hypertensive heart by upregulation of IL-6 productions by activating NF-kappaB via integrin αVβ3 on macrophage.

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