Chronic angiotensin-(1–7) prevents cardiac fibrosis in DOCA-salt model of hypertension

2006 ◽  
Vol 290 (6) ◽  
pp. H2417-H2423 ◽  
Author(s):  
Justin L. Grobe ◽  
Adam P. Mecca ◽  
Haoyu Mao ◽  
Michael J. Katovich
Keyword(s):  
Blood Pressure ◽  
Drinking Water ◽  
Cardiac Hypertrophy ◽  
Cross Sections ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Collagen Deposition ◽  
Sprague Dawley ◽  
Artery Cannulation ◽  
Blood Pressure Responses

Cardiac remodeling is a hallmark hypertension-induced pathophysiology. In the current study, the role of the angiotensin-(1–7) fragment in modulating cardiac remodeling was examined. Sprague-Dawley rats underwent uninephrectomy surgery and were implanted with a deoxycorticosterone acetate (DOCA) pellet. DOCA animals had their drinking water replaced with 0.9% saline solution. A subgroup of DOCA-salt animals was implanted with osmotic minipumps, which delivered angiotensin-(1–7) chronically (100 ng·kg−1·min−1). Control animals underwent sham surgery and were maintained on normal drinking water. Blood pressure was measured weekly with the use of the tail-cuff method, and after 4 wk of treatment, blood pressure responses to graded doses of angiotensin II were determined by direct carotid artery cannulation. Ventricle size was measured, and cross sections of the heart ventricles were paraffin embedded and stained using Masson's Trichrome to measure interstitial and perivascular collagen deposition and myocyte diameter. DOCA-salt treatment caused significant increases in blood pressure, cardiac hypertrophy, and myocardial and perivascular fibrosis. Angiotensin-(1–7) infusion prevented the collagen deposition effects without any effect on blood pressure or cardiac hypertrophy. These results indicate that angiotensin-(1–7) selectively prevents cardiac fibrosis independent of blood pressure or cardiac hypertrophy in the DOCA-salt model of hypertension.

scholarly journals Different blood pressure responses in hypertensive rats following chemerin mRNA inhibition in dietary high fat compared to dietary high-salt conditions

2019 ◽  
Vol 51 (11) ◽  
pp. 553-561 ◽  
Author(s):  
David J. Ferland ◽  
Emma D. Flood ◽  
Hannah Garver ◽  
Steve T. Yeh ◽  
Stanley Riney ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Antisense Oligonucleotides ◽  
Reduce Blood Pressure ◽  
High Salt ◽  
Whole Body ◽  
Sprague Dawley ◽  
High Fat ◽  
Hypertensive Rats ◽  
Blood Pressure Responses ◽  
Antihypertensive Treatments

Chemerin is a contractile adipokine, produced in liver and fat, and removal of the protein by antisense oligonucleotides (ASO) lowers blood pressure in the normal Sprague Dawley rat. In humans, chemerin is positively associated with blood pressure and obesity so we hypothesized that in a model of hypertension derived from high-fat (HF) feeding, the chemerin ASO would reduce blood pressure more than a high-salt (HS) model. Male Dahl S rats were given a HF (60% kcal fat; age 3–24 wk) or HS diet (4% salt; age 20–24 wk to match age and blood pressure of HF animals). Scrambled control, whole body, or liver-specific ASOs that knock down chemerin were delivered subcutaneously once per week for 4 wk with tissue and blood collected 2 days after the last injection. Conscious blood pressure was measured 24 h/day by radiotelemetry. By the end of whole body ASO administration, blood pressure of HF animals had fallen 29 ± 2 mmHg below baseline, while blood pressure of HS-diet animals fell by only 12 ± 4 mmHg below baseline. Administration of a liver-specific ASO to HF Dahl S resulted in a 6 ± 2 mmHg fall in blood pressure below baseline. Successful knockdown of chemerin in both the whole body and liver-specific administration was confirmed by Western and PCR. These results suggest that chemerin, not derived from liver but potentially from adipose tissue, is an important driver of hypertension associated with high fat. This knowledge could lead to the development of antihypertensive treatments specifically targeted to obesity-associated hypertension.

Abstract 142: A Fructose-but Not a Glucose-enriched Diet, Induces a Salt-dependent Increase in Blood Pressure and Enhances NKCC2 Phosphorylation in Normal Rats

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Keyona N King-Medina ◽  
Emily Henson ◽  
Pablo Ortiz
Keyword(s):  
Blood Pressure ◽  
Drinking Water ◽  
Salt Intake ◽  
Caloric Intake ◽  
High Salt ◽  
Human Consumption ◽  
Thick Ascending Limb ◽  
Sprague Dawley ◽  
High Fructose ◽  
High Salt Intake

Human consumption of fructose as a sweetener has increased in the past 30 years. High fructose intake has been implicated in the development of hypertension, diabetes, and obesity. In the US, the upper 10th percentile of the population consumes up to 40% of their caloric intake from added sugars, in which fructose represents half of these. Fructose metabolism is strikingly different from that of glucose. Yet, the effect of a fructose or glucose-enriched diet in salt handling by the kidney, affecting blood pressure, and its interaction with high salt intake has been poorly studied. In genetic models of salt-sensitive hypertension, the activity of the Na + /K + /2Cl - cotransporter (NKCC2) in the thick ascending limb (TAL) is abnormally enhanced. We hypothesized that chronic fructose in drinking water induces a salt-dependent increase in blood pressure and stimulates NKCC2 during high salt intake in normal rats. Sprague-Dawley rats were given 20% fructose or 20% glucose in drinking water for 1 week after which a high salt (HS) diet (4% Na + in chow) was started for 3 weeks. When we measured systolic blood pressure (SBP) by tail cuff plethysmography in fructose-fed and glucose-fed rats on a HS diet, only the fructose-fed rats had an increased SBP from 120±10 to 132±6 mmHg on day 7 of HS (p<0.01). SBP continued to increase up to 144±18 mmHg after 3 weeks (p<0.01 vs glucose). Fructose or glucose alone did not increase SBP after 4 weeks. We then repeated the protocol using radiotelemetry to monitor the blood pressure (BP). In rats fed fructose, by day 5 of HS the SBP increased by 12±3 mmHg (p<0.02) and SBP remained elevated for 3 weeks (delta: 10±2.5 mmHg, n=3). In rats fed glucose, a HS diet did not significantly change SBP for 3 weeks (n=5). Moreover, NKCC2 activity in the TAL is enhanced by phosphorylation at Thr96, 101. We found that NKCC2 phosphorylation was higher in rats fed fructose plus HS (p<0.02) but not in rats fed glucose plus HS for 3 weeks (HS: 100, fructose+HS: 250±40%, glucose+HS: 95±10%). Therefore, we conclude that a high fructose (but not a glucose) diet in normal rats induces a salt-dependent increase in BP independently from caloric intake. Thus, the increase in BP may in part be due to the stimulation of NKCC2 phosphorylation in the TAL by fructose.

scholarly journals MicroRNA as a Therapeutic Target in Cardiac Remodeling

2017 ◽  
Vol 2017 ◽  
pp. 1-25 ◽  
Author(s):  
Chao Chen ◽  
Murugavel Ponnusamy ◽  
Cuiyun Liu ◽  
Jinning Gao ◽  
Kun Wang ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Heart Diseases ◽  
Myocardial Remodeling ◽  
Cardiac Tissues ◽  
Rna Molecules ◽  
Mirnas Expression ◽  
The Impact

MicroRNAs (miRNAs) are small RNA molecules that contain 18–25 nucleotides. The alterations in their expression level play crucial role in the development of many disorders including heart diseases. Myocardial remodeling is the final pathological consequence of a variety of myocardial diseases. miRNAs have central role in regulating pathogenesis of myocardial remodeling by modulating cardiac hypertrophy, cardiomyocytes injury, cardiac fibrosis, angiogenesis, and inflammatory response through multiple mechanisms. The balancing and tight regulation of different miRNAs is a key to drive the cellular events towards functional recovery and any fall in this leads to detrimental effect on cardiac function following various insults. In this review, we discuss the impact of alterations of miRNAs expression on cardiac hypertrophy, cardiomyocytes injury, cardiac fibrosis, angiogenesis, and inflammatory response. We have also described the targets (receptors, signaling molecules, transcription factors, etc.) of miRNAs on which they act to promote or attenuate cardiac remodeling processes in different type cells of cardiac tissues.

Male and female rats express similar blood pressure responses to “push-pull” gravitational stress

2002 ◽  
Vol 93 (6) ◽  
pp. 2029-2033 ◽  
Author(s):  
Amy L. Hakeman ◽  
Don D. Sheriff
Keyword(s):  
Blood Pressure ◽  
Female Rats ◽  
Sprague Dawley ◽  
Similar Extent ◽  
Axis Of Rotation ◽  
Male And Female Rats ◽  
Gravitational Stress ◽  
Subsequent Exposure ◽  
Males And Females ◽  
Blood Pressure Responses

Brief exposure to −Gz (“push”) reduces eye-level blood pressure (elbp) during subsequent exposure to +Gz(“pull”). This is called the “push-pull effect.” To evaluate the influence of gender and the axis of rotation (pitch vs. roll) on the push-pull effect, 10 isoflurane-anesthetized male and 10 female Sprague-Dawley rats were restrained supine on a heated tilt board. Rats were subjected to two G profiles: a control profile consisting of rotation from 0 Gz to 90° head-up tilt (+1 Gz) for 10 s and a push-pull profile consisting of rotation from 0 Gz to 90° head-down tilt (−1 Gz) for 2 s immediately preceding 10 s of +1 Gz stress. A total of 16 tilts consisting of equal numbers of control and push-pull trials and equal numbers of pitch and roll rotations were imposed by using a counterbalanced design. Gender exerted a significant effect on baseline (0 Gz) ELBP (pressure was ∼4 mmHg higher in females). In males and females, ELBP rose to a similar extent (∼8 mmHg) during push, fell to a similar extent (∼18 mmHg) during control +Gz stress, and fell to a similar extent (∼22 mmHg) during push-pull +Gz stress. Altering the axis of rotation between the x-axis (roll) and the y-axis (pitch) did not influence the results. Thus males and females exhibit a push-pull effect; however, gender and axis of rotation do not appear to influence the push-pull effect in anesthetized rats subjected to tilting.

Abstract 392: Blood Pressure Variability: An Independent Marker to Morbimortality

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Janaina Paulini ◽  
Fernanda Nishi ◽  
Luciana Jorge ◽  
Romulo Pires ◽  
Eduardo Moacir Krieger ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Relaxation Time ◽  
Cardiac Index ◽  
Left Ventricle ◽  
Cardiac Hypertrophy ◽  
Blood Pressure Variability ◽  
Cardiac Fibrosis ◽  
Systolic Ejection ◽  
Cardiac Blood

Introdution: The purpose of this study was to investigate the mechanisms enrolled in the relationship between increased BP variability, heart damage and mortality in different pathophysiological conditions as hypertension, heart failure and myocardial infarction. Method: Wistar rats were divided into control and S (n=10, 8weeks). Sinoaortic denervation (S) was performed using the method previously described. BP and HR were analysed using a data acquisition system. BP variability was analyzed by spectral analysis. Left ventricle systolic ejection and diastolic isovolumetric relaxation time were evaluated by echocardiography. Cardiac fibrosis and cardiomyocytes diameter were quantified by histological analysis. CO, cardiac blood flow and cardiac index were evaluated using colored microspheres. Result: No difference was observed in BP and HR (C:104±2 vs 106±2 mmHg; C:313±7 vs 329±3 bpm), while BP variability was increased after S (C:29±2 vs 46*±5 mmHg). Left ventricle systolic ejection was decreased (C:72±0.9 vs 64*±1.5%) and diastolic isovolumetric relaxation time (C:21±1 vs 35*±1 ms) was increased in S group. Moreover, it was observed a reduction in CO (C:111±5 vs 81*±5 mL/min), an increase in cardiac resistance (C:35±1.8 vs 66*±2.6 mL/min/mmHg) and a decreased in cardiac index (C:320±9.7 vs 270*±8.1 l/min/m2) in S group. Those alterations resulted in decreased myocardial blood flow (C:3.47±0.21 vs 1.6*±0.3 mL/min/g). An increased cardiomyocytes diameter (C:14.9±0.3 vs 18.9*±0.3μm),fibrosis (C:0.85±0.08 vs 3.28*±0.2%) and cardiac hypertrophy index (C:3.07±0.06 vs 3.97*±0.1) were observed in S group.The association of all those changes lead to a 72% higher mortality in animals with increased blood pressure variability.(*p<0.03) Conclusion: An increased BP variability resulted in a reduced cardiac blood flow, CO and cardiac index and an increased in myocardial resistance this adaptations occours as a attempt to homeostasis maintenance. Howerer, the morphofunctional alterations showed a diastolic dysfunction, increased cardiac hypertrophy index and fibrosis as a resulted. These adjustements could be a determinant factor in cardiac damage and in mortality in different pathological conditions, independently of BP levels.

Induction of Oxidative Stress by Glutathione Depletion Causes Severe Hypertension in Normal Rats

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 688-688
Author(s):  
Nosratola D Vaziri ◽  
Xiu Q Wang ◽  
Fariba Oveisi ◽  
Behdad Rad
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Drinking Water ◽  
Urinary Excretion ◽  
Antioxidant Therapy ◽  
Glutathione Depletion ◽  
Hepatic Tissue ◽  
Control Group ◽  
Sprague Dawley ◽  
Arterial Blood

59 Several recent studies have shown that certain forms of genetic and acquired hypertension (HTN) are associated with oxidative stress and respond favorably to antioxidant therapy. We hypothesize that oxidative stress, per se, may cause HTN via (among other mechanisms) enhanced oxidation and inactivation of nitric oxide (NO). To test this hypothesis, Sprague-Dawley rats were subjected to oxidative stress by glutathione (GSH) depletion using GSH synthase inhibitor, buthionine sulfoximine (BSO, 30 mmol/L in drinking water), for two weeks. The control group was given drug-free drinking water. In parallel experiments, subgroups of animals were provided vitamin E-fortified chow and vitamin C-supplemented drinking water. Arterial blood pressure, urinary excretion of NO metabolites (NO 2 +NO 3 , NOx), and liver tissue GSH were measured. In addition, plasma, kidney, heart, liver and aorta were tested by Western blot analysis for nitrotyrosine, which is the footprint of NO inactivation by reactive oxygen species (ROS). The BSO-treated group showed a three-fold fall in hepatic tissue GSH content (0.99±0.3 vs 3.4±0.3 μmol/g wet tissue, P<0.001), a marked elevation in blood pressure (203±3 vs 120±2 mmHg, P<0.001) and a significant reduction in urinary excretion of NO metabolites, nitrate + nitrite (316±23 vs 595±29 μmol/g creatinine, P<0.01), suggesting depressed NO availability. This was associated with a significant accumulation in all tested tissues of nitrotyrosine (P<0.05 for all comparisons). Administration of vitamins E+C ameliorated HTN (156±4 mmHg, P<0.01), improved urinary NOx excretion (392±28 μmol/g creatinine, P<0.05) and mitigated nitrotyrosine accumulation (despite persistent GSH depletion) in the BSO-treated animals. However, vitamins E+C treatment had no effect on any of the above parameters in the control group (data not shown). In conclusion, GSH depletion resulted in perturbation of the NO system and severe HTN in normal animals. The effects of BSO were mitigated by concomitant antioxidant therapy despite GSH depletion, supporting the notion that oxidative stress was involved in the pathogenesis of HTN in this model.

scholarly journals Gender differences in adenine-induced chronic kidney disease and cardiovascular complications in rats

2014 ◽  
Vol 307 (11) ◽  
pp. F1169-F1178 ◽  
Author(s):  
Vishal Diwan ◽  
David Small ◽  
Kate Kauter ◽  
Glenda C. Gobe ◽  
Lindsay Brown
Keyword(s):  
Blood Pressure ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Cardiac Hypertrophy ◽  
Kidney Function ◽  
Cardiac Fibrosis ◽  
Kidney Damage ◽  
Plasma Testosterone ◽  
Male And Female ◽  
Males And Females

Gender contributes to differences in incidence and progression of chronic kidney disease (CKD) and associated cardiovascular disease. To induce kidney damage in male and female Wistar rats ( n = 12/group), a 0.25% adenine diet for 16 wk was used. Kidney function (blood urea nitrogen, plasma creatinine, proteinuria) and structure (glomerular damage, tubulointerstitial atrophy, fibrosis, inflammation); cardiovascular function (blood pressure, ventricular stiffness, vascular responses, echocardiography) and structure (cardiac fibrosis); plasma testosterone and estrogen concentrations; and protein expression for oxidative stress [heme oxygenase-1, inflammation (TNF-α), fibrosis (transforming growth factor-β), ERK1/2, and estrogen receptor-α (ER-α)] were compared in males and females. Adenine-fed females had less decline in kidney function than adenine-fed males, although kidney atrophy, inflammation, and fibrosis were similar. Plasma estrogen concentrations increased and plasma testosterone concentrations decreased in adenine-fed males, with smaller changes in females. CKD-associated molecular changes in kidneys were more pronounced in males than females except for expression of ER-α in the kidney, which was completely suppressed in adenine-fed males but unchanged in adenine-fed females. Both genders showed increased blood pressure, ventricular stiffness, and cardiac fibrosis with the adenine diet. Cardiovascular changes with adenine were similar in males and females, except males developed concentric, and females eccentric cardiac hypertrophy. In hearts from adenine-fed male and female rats, expression of ER-α and activation of the ERK1/2 pathway were increased, in part explaining changes in cardiac hypertrophy. In summary, adenine-induced kidney damage may be increased in males due to the suppression of ER-α.

scholarly journals Angiotensin II receptor blocker LCZ696 attenuates cardiac remodeling through the inhibition of the ERK signaling pathway in mice with pregnancy-associated cardiomyopathy

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yi Wang ◽  
Zhiheng Guo ◽  
Yongmei Gao ◽  
Ping Liang ◽  
Yanhong Shan ◽  
...  
Keyword(s):  
Survival Rate ◽  
Cardiac Hypertrophy ◽  
Signaling Pathway ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Cardiac Injury ◽  
Erk Signaling ◽  
Ang Ii ◽  
Total Survival

Abstract Pregnancy-associated cardiomyopathy (PAH) represents a pregnancy-associated myocardial disease that is characterized by the progression of heart failure due to marked left ventricular systolic dysfunction. Compelling evidence has highlighted the potential of angiotensin (Ang) receptor inhibitors as therapeutic targets in PAH treatment. The present study aims to elucidate the molecular mechanisms underlying Ang II receptor inhibitor LCZ696 treatment in PAH. Initially, a PAH mouse model was induced, followed by intraperitoneal injection of LCZ696. Subsequently, cardiomyocytes and fibroblasts were isolated, cultured, and treated with Ang II and LCZ696, followed by detection of the total survival rate, cardiac injury, cardiac fibrosis and apoptosis. Moreover, in order to quantify the cardiac hypertrophy and fibrosis degree of cardiac fibroblasts, the expression levels of markers of cardiac hypertrophy (ANP, βMHC and TIMP2) and markers of fibrosis (collagen I, collagen III and TGF-β) were evaluated. Furthermore, the potential effect of LCZ696 on the extracellular signal-regulated kinase (ERK) signaling pathway was examined. The acquired findings revealed that LCZ696 increased the total survival rate of PAH mice, but decreased cardiac injury, cardiac fibrosis, and apoptosis in vitro. LCZ696 attenuated cardiac injury induced by Ang II through the inhibition the expression of markers of cardiac hypertrophy, fibrosis and apoptosis by inhibiting ERK phosphorylation in vivo and in vitro. Altogether, LCZ676 could potentially alleviate cardiac remodeling in mice with PAH via blockade of the ERK signaling pathway activation. Our findings suggest that LCZ696 could be a potential target for PAH therapy.

Copper-induced reduction in myocardial fibrosis is associated with increased matrix metalloproteins in a rat model of cardiac hypertrophy

Metallomics ◽  
2018 ◽  
Vol 10 (1) ◽  
pp. 201-208 ◽  
Author(s):  
Yinjie Liu ◽  
Ying Xiao ◽  
Jiaming Liu ◽  
Li Feng ◽  
Y. James Kang
Keyword(s):  
Cardiac Hypertrophy ◽  
Myocardial Fibrosis ◽  
Rat Model ◽  
Cardiac Fibrosis ◽  
Collagen Deposition ◽  
Matrix Metalloproteins

AAC induces Cu loss from the heart and depressed MMP-2 in combination with increased TIMPs, leading to increased collagen deposition. TETA replenishes Cu in the heart, increases MMP-2, and decreases TIMP-1 and -2, collectively resulting in reduction in cardiac fibrosis.

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