Remodeling In Hypertensive Rats Research Articles

Asprosin contributes to vascular remodeling in hypertensive rats via superoxide signaling.

Proliferation and migration of vascular smooth muscle cells (VSMCs) contribute to vascular remodeling. Asprosin, a newly discovered protein hormone, is involved in metabolic diseases. Little is known about the roles of asprosin in cardiovascular diseases. This study focused on the role and mechanism of asprosin on VSMC proliferation and migration, and vascular remodeling in a rat model of hypertension. VSMCs were obtained from the aortic media of 8-week-old male Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Asprosin was upregulated in the VSMCs of SHR. For in vitro studies, asprosin promoted VSMC proliferation and migration of WKY and SHR, and increased Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activity, NOX1/2/4 protein expressions and superoxide production. Knockdown of asprosin inhibited the proliferation, migration, NOX activity, NOX1/2 expressions and superoxide production in the VSMCs of SHR. The roles of asprosin in promoting VSMC proliferation and migration were not affected by hydrogen peroxide scavenger, but attenuated by superoxide scavenger, selective NOX1 or NOX2 inhibitor. Toll-like receptor 4 (TLR4) was upregulated in SHR, TLR4 knockdown inhibited asprosin overexpression-induced proliferation, migration and oxidative stress in VSMCs of WKY and SHR. Asprosin was upregulated in arteries of SHR, and knockdown of asprosin in vivo not only attenuated oxidative stress and vascular remodeling in aorta and mesentery artery, but also caused a subsequent persistent antihypertensive effect in SHR. Asprosin promotes VSMC proliferation and migration via NOX-mediated superoxide production. Inhibition of endogenous asprosin expression attenuates VSMC proliferation and migration, and vascular remodeling of SHR.

Wogonin attenuates vascular remodeling by inhibiting smooth muscle cell proliferation and migration in hypertensive rat.

Wogonin, extracted from the roots of Scutellaria baicalensis Georgi, has been shown to suppress collagen deposition in spontaneously hypertensive rats (SHRs). This study was performed to investigate the role and mechanism of wogonin underlying vascular remodeling in SHRs. After injection of SHRs with 40 mg/kg of wogonin, blood pressure in rats was measured once a week. Masson's trichrome staining was conducted to observe the changes in aortas and mesenteric arteries. Vascular smooth muscle cells (VSMCs) isolated from rat thoracic aortas were treated with Angiotensin II (Ang II; 100 nM) in the presence or absence of varying concentrations of wogonin. The viability and proliferation of VSMCs were examined using Cell Counting Kit-8 assay and 5-ethynyl-2'-deoxyuridine assay, respectively. The migration of VSMCs was examined using wound healing assay and transwell assay. We found that wogonin administration alleviated hypertension, increased lumen diameter, and reduced the thickness of the arterial media in SHRs. Ang II treatment enhanced the viability of VSMCs, which was inhibited by wogonin in a concentration-dependent manner. Wogonin reversed Ang II-induced increases in the viability, proliferation, and migration of VSMCs. Moreover, wogonin inhibited Ang II-induced activation of mitogen-activated protein kinase (MAPK) signaling in VSMCs. Overall, wogonin repressed the proliferative and migratory capacity of VSMCs by regulating the MAPK signaling pathway, thereby attenuating vascular remodeling in hypertensive rats, indicating that wogonin might be a therapeutic agent for the treatment of vascular diseases.

PDZK1 improves ventricular remodeling in hypertensive rats by regulating the stability of the Mas receptor.

Ventricular remodeling is one of the main causes of mortality from heart failure due to hypertension. Exploring its mechanism and finding therapeutic targets have become urgent scientific problems to be solved. A number of studies have shown that Mas, as an Ang-(1-7) specific receptor, was significantly reduced in myocardial tissue of rats undergoing hypertensive ventricular remodeling. It has been reported that Mas receptor levels are significantly downregulated in myocardium undergoing ventricular remodeling, but studies focused on intracellular and post-translational modifications of Mas are lacking. The results of this research are as follows: (1) PDZK1 interacts with the carboxyl terminus of Mas through its PDZ1 domain; (2) the expression of PDZK1 and Mas is decreased in rats undergoing hypertensive ventricular remodeling, and PDZK1 upregulation can ameliorate hypertensive myocardial fibrosis and myocardial hypertrophy; (3) PDZK1 enhances the stability of Mas protein through the proteasome pathway, and the proteasome inhibitor MG132 promotes hypertensive ventricular remodeling. PDZK1 improves ventricular remodeling in hypertensive rats by regulating Mas receptor stability. This study provides a scientific basis for the prevention and treatment of ventricular remodeling.

Limonin ameliorates cardiovascular dysfunction and remodeling in hypertensive rats

AimsLimonin is a tetracyclic triterpenoid isolated from citrus fruits. Here, the effects of limonin on cardiovascular abnormalities in nitric oxide-deficient rats induced by Nω-Nitrol-arginine methyl ester (L-NAME) were explored. Main methodsMale Sprague Dawley rats were given L-NAME (40 mg/kg, drinking water) for 3 weeks and then treated daily with polyethylene glycol (vehicle), limonin (50 or 100 mg/kg) or telmisartan (10 mg/kg) for two weeks. Key findingsLimonin (100 mg/kg) markedly reduced L-NAME-induced hypertension, cardiovascular dysfunction and remodeling in rats (P < 0.05). Increases in systemic angiotensin-converting enzyme (ACE) activity and angiotensin II (Ang II) and a reduction in circulating ACE2 were restored in hypertensive rats treated with limonin (P < 0.05). Reductions in antioxidant enzymes and nitric oxide metabolites (NOx) and increases in oxidative stress components induced by L-NAME were relieved by limonin treatment (P < 0.05). Limonin suppressed the increased expression of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 in cardiac tissue and circulating TNF-α in rats that received L-NAME (P < 0.05). Changes in Ang II receptor type I (AT1R), Mas receptor (MasR), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB) and NADPH oxidase subunit 2 (gp91phox) protein expression in cardiac and aortic tissue were normalized by limonin (P < 0.05). SignificanceIn conclusion, limonin ameliorated L-NAME-induced hypertension, cardiovascular dysfunction and remodeling in rats. These effects were relevant to restorations of the renin-angiotensin system, oxidative stress and inflammation in NO-deficient rats. The molecular mechanisms are associated with the modulation of AT1R, MasR, NF-ĸB and gp91phox protein expression in cardiac and aortic tissue.

Imperatorin derivative OW1, a new vasoactive compound, attenuates cell proliferation and migration by inhibiting Nox1-mediated oxidative stress.

Reactive oxygen species (ROS) are involved in the structural remodelling of vascular segments and vascular beds. We identified a new imperatorin derivative, OW1, which has significant effects on vasodilation and inhibits vascular remodelling in hypertensive rats. In this study, we investigated whether OW1 inhibits vascular cell proliferation and migration by attenuating Nox1-ROS signalling. Vascular smooth muscle cells (VSMCs) were treated with OW1 (1, 3 and 10 µmol/L) for 24 h incubation, and it has been analysed for proliferation and peroxidation levels. Moreover, the mRNA and protein levels of nicotinamide adenine dinucleotide phosphate oxidase (Noxs) were measured by RT-PCR and western blot. Furthermore, Nox1-ROS-MAPK/MMP mediated cell proliferation was detected by western blot. Ang II-induced increases in the levels of peroxidation and Noxs in VSMCs were also inhibited by OW1. OW1 attenuates cell proliferation and migration through the MAPK pathway and MMPs. OW1 treatment had no significant effects on cell migration, ROS levels, or the expression of phosphorylated MAPKs in VSMCs when Nox1 was knocked down. OW1 reduced ROS levels and expression of phosphorylated MAPKs in NIH3T3 cells with a Nox1 overexpression plasmid. OW1 may inhibit vascular remodelling by downregulating the Nox1-ROS-MAPK/MMP signalling pathway.

Renal denervation reduces atrial remodeling in hypertensive rats with metabolic syndrome

Atrial fibrillation (AF) is highly prevalent in hypertensive patients with metabolic syndrome and is related to inflammation and activation of the sympathoadrenergic system. The multi-ligand Receptor-for-Advanced-Glycation-End-products (RAGE) activates inflammation-associated tissue remodeling and is regulated by the sympathetic nervous system. Its counterpart, soluble RAGE (sRAGE), serves as anti-inflammatory decoy receptor with protective properties. We investigated the effect of sympathetic modulation by renal denervation (RDN) on atrial remodeling, RAGE/sRAGE and RAGE ligands in metabolic syndrome. RDN was performed in spontaneously hypertensive obese rats (SHRob) with metabolic syndrome compared with lean spontaneously hypertensive rats (SHR) and with normotensive non-obese control rats. Blood pressure and heart rate were measured by telemetry. The animals were killed 12 weeks after RDN. Left atrial (LA) and right atrial (RA) remodeling was assessed by histological analysis and collagen types. Sympathetic innervation was measured by tyrosine hydroxylase staining of atrial nerve fibers, RAGE/sRAGE, RAGE ligands, cytokine expressions and inflammatory infiltrates were analyzed by Western blot and immunofluorescence staining. LA sympathetic nerve fiber density was higher in SHRob (+44%) versus controls and reduced after RDN (-64% versus SHRob). RAGE was increased (+718%) and sRAGE decreased (− 62%) in SHRob as compared with controls. RDN reduced RAGE expression (− 61% versus SHRob), significantly increased sRAGE levels (+162%) and induced a significant decrease in RAGE ligand levels in SHRob (− 57% CML and − 51% HMGB1) with reduced pro-inflammatory NFkB activation (− 96%), IL-6 production (− 55%) and reduced inflammatory infiltrates. This led to a reduction in atrial fibrosis (− 33%), collagen type I content (− 72%), accompanied by reduced LA myocyte hypertrophy (− 21%). Transfection experiments on H9C2 cardiomyoblasts demonstrated that RAGE is directly involved in fibrosis formation by influencing cellular production of collagen type I. In conclusion, suppression of renal sympathetic nerve activity by RDN prevents atrial remodeling in metabolic syndrome by reducing atrial sympathetic innervation and by modulating RAGE/sRAGE balance and reducing pro-inflammatory and pro-fibrotic RAGE ligands, which provides a potential therapeutic mechanism to reduce the development of AF.

Protective Effect of Campbell early Leaf extract on Cardiovascular Dysfunction in Spontaneously Hypertensive Rats

The Campbell early is a grapevine that has neuroprotective, antioxidant, hepatoprotective, and anticarcinogenic activity. However, the effect of Campbell early leaf on the cardiovascular system is yet to be ascertained. The present study was designed to investigate the effects of Campbell early leaf extract (CL) on cardiovascular remodeling in spontaneously hypertensive rats. Experiments were performed in rats and were randomly divided into the following groups: Wistar Kyoto rat (WKY), normal control group; spontaneously hypertensive rats (SHR), negative control group; SHR + Losa (positive control groups, losartan 10 mg/kg,) and SHR + CL (100 mg/kg). CL was orally administered daily for 4 weeks. The CL treatment significantly improved blood pressure, electrocardiographic parameters, and echocardiogram parameters compared to hypertensive rats. Additionally, the left ventricular (LV) remodeling and LV dysfunction were significantly improved in CL-treated hypertensive rats. Furthermore, an increase in fibrotic area has been observed in hypertensive rats compared with WKY. However, administration of CL significantly attenuated cardiac fibrosis in hypertensive rats. Moreover, CL suppressed the expression of high mobility group box 1, toll-like receptor 4, myeloid differentiation primary response 88, nuclear factor kappa-light-chain-enhancer of activated B cells, tumor necrosis factor alpha, interleukin-6, receptor for advanced glycation end products, and extracellular signal-regulated kinases induced by hypertensive rats, resulting in improved vascular remodeling. Therefore, these results suggest that CL can improve the cardiovascular remodeling in hypertensive rats, and the mechanisms may be related to the suppressive effect of CL on HMGB1-TLR4 signaling in the cardiovascular system. Thus, the protective role of the traditional herbal medicine CL may provide new insights into the development of therapeutic drugs on the development of hypertensive cardiovascular dysfunction.

Inhibition of miR-135a-5p attenuates vascular smooth muscle cell proliferation and vascular remodeling in hypertensive rats.

Proliferation of vascular smooth muscle cells (VSMCs) greatly contributes to vascular remodeling in hypertension. This study is to determine the roles and mechanisms of miR-135a-5p intervention in attenuating VSMC proliferation and vascular remodeling in spontaneously hypertensive rats (SHRs). MiR-135a-5p level was raised, while fibronectin type III domain-containing 5 (FNDC5) mRNA and protein expressions were reduced in VSMCs of SHRs compared with those of Wistar-Kyoto rats (WKYs). Enhanced VSMC proliferation in SHRs was inhibited by miR-135a-5p knockdown or miR-135a-5p inhibitor, but exacerbated by miR-135a-5p mimic. VSMCs of SHRs showed reduced myofilaments, increased or even damaged mitochondria, increased and dilated endoplasmic reticulum, which were attenuated by miR-135a-5p inhibitor. Dual-luciferase reporter assay shows that FNDC5 was a target gene of miR-135a-5p. Knockdown or inhibition of miR-135a-5p prevented the FNDC5 downregulation in VSMCs of SHRs, while miR-135a-5p mimic inhibited FNDC5 expressions in VSMCs of both WKYs and SHRs. FNDC5 knockdown had no significant effects on VSMC proliferation of WKYs, but aggravated VSMC proliferation of SHRs. Exogenous FNDC5 or FNDC5 overexpression attenuated VSMC proliferation of SHRs, and prevented miR-135a-5p mimic-induced enhancement of VSMC proliferation of SHR. MiR-135a-5p knockdown in SHRs attenuated hypertension, normalized FNDC5 expressions and inhibitedvascular smooth muscle proliferation, and alleviated vascular remodeling. These results indicate that miR-135a-5p promotes while FNDC5 inhibits VSMC proliferation in SHRs. Silencing of miR-135a-5p attenuates VSMC proliferation and vascular remodeling in SHRs via disinhibition of FNDC5 transcription. Either inhibition of miR-135a-5p or upregulation of FNDC5 may be a therapeutically strategy in attenuating vascular remodeling and hypertension.

Protective Effect of Vitis labrusca Leaves Extract on Cardiovascular Dysfunction through HMGB1-TLR4-NFκB Signaling in Spontaneously Hypertensive Rats.

The Vitis labrusca is a grapevine that has antioxidant, neuroprotective, hepatoprotective, and anticarcinogenic activity. However, the effect of Vitis labrusca leaves on the cardiovascular system is yet to be ascertained. The present study was designed to investigate the effects of Vitis labrusca leaves extract (HP1) on cardiovascular remodeling in spontaneously hypertensive rats. Experiments were performed in rats and were randomly divided into the following groups: Wistar Kyoto rat (WKY), normal control group; spontaneously hypertensive rats (SHR), negative control group; SHR + Losa, positive control group (losartan, 10 mg/kg/daily, AT1 receptor blocker) and SHR + HP1 (100 mg/kg/daily). HP1 was orally administered daily for 4 weeks. The HP1 treatment significantly improved blood pressure, electrocardiographic parameters, and echocardiogram parameters compared to hypertensive rats. Additionally, the left ventricular (LV) remodeling and LV dysfunction were significantly improved in HP1-treated hypertensive rats. Furthermore, an increase in fibrotic area has been observed in hypertensive rats compared with WKY. However, administration of HP1 significantly attenuated cardiac fibrosis in hypertensive rats. Moreover, HP1 suppressed the expression of high mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), receptor for advanced glycation end products (RAGE), and extracellular signal-regulated kinases (ERK1/2) induced by hypertensive rats, resulting in improved vascular remodeling. Therefore, these results suggest that HP1 can improve the cardiovascular remodeling in hypertensive rats, and the mechanisms may be related to the suppressive effect of HP1 on HMGB1-TLR4-NFκB signaling in the cardiovascular system. Thus, the protective role of the traditional herbal medicine HP1 may provide new insights into the development of therapeutic drugs on the development of hypertensive cardiovascular dysfunction.

Tangeretin mitigates l-NAME-induced ventricular dysfunction and remodeling through the AT1R/pERK1/2/pJNK signaling pathway in rats.

Tangeretin is a citrus flavonoid that exerts several beneficial effects, including anti-inflammation, anti-oxidation and neuroprotection. In this study, the aim was to test the effect of tangeretin on Nω-Nitro-l-arginine methyl ester (l-NAME)-induced high blood pressure, and left ventricular dysfunction and remodeling in rats. Rats were divided into five groups (n = 8 per each group): a control group, an l-NAME group and three l-NAME groups treated with tangeretin (15 mg kg-1) or tangeretin (30 mg kg-1) or captopril (5 mg kg-1) for the final two weeks. After five weeks of experiment, l-NAME groups had high systolic blood pressures, and ventricular dysfunction and remodeling. Overexpression of angiotensin II type 1 receptor, phosphorylated-extracellular-regulated kinase 1/2 (pERK1/2), and phosphorylated-c-Jun N-terminal kinase (pJNK) protein but downregulation of endothelial nitric oxide synthase (eNOS) protein expression in ventricular tissues were observed in hypertensive rats while the protein expression of phosphorylated-mitogen activated protein kinase p38 did not differ among groups. The decrease in plasma NOx and increase in vascular superoxide generation, plasma malondialdehyde, angiotensin-converting enzyme activity and angiotensin II levels were found in hypertensive rats. These alterations were suppressed in hypertensive rats treated with tangeretin or captopril. In conclusion, tangeretin exhibits antihypertensive effects and alleviates ventricular dysfunction and remodeling in hypertensive rats. These effects are associated with the inhibition of renin angiotensin system activation and restoration of pERK1/2, pJNK, and eNOS protein expressions along with reduced oxidative stress and increased NO bioavailability.

Long non-coding RNA MALAT1 promotes cardiac remodeling in hypertensive rats by inhibiting the transcription of MyoD.

Hypertension is the leading preventable cause of premature deaths worldwide. Although long non-coding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (MALAT1) has been identified to play important roles in the development of cardiovascular diseases, the regulatory function of lncRNA MALAT1 in hypertension remains poorly understood. This study aimed to explore the role of lncRNA MALAT1 in spontaneously hypertensive rats (SHRs). LncRNA MALAT1 was determined to be elevated and MyoD to be reduced in myocardial tissues and thoracic aortic vascular tissues of SHRs. Over-expression of lncRNA MALAT1 caused severe myocardial fibrosis in SHRs. In addition, lncRNA MALAT1 over-expression in vitro enhanced arterial smooth muscle cells (ASMCs) activity and fibrosis of SHRs, which, was rescued by over-expressed MyoD. Furthermore, lncRNA MALAT1 transcripts were found to be highly enriched in the nucleus, and lncRNA MALAT1 suppressed the transactivation of MyoD. Moreover, lncRNA MALAT1 was found to recruit Suv39h1 to MyoD-binding loci, leading to H3K9me3 trimethylation and down-regulation of the target gene. Taken conjointly, this study revealed an important role of lncRNA MALAT1 in promoting cardiac remodeling in hypertensive rats by inhibiting the transcription of MyoD. These results highlight the value of lncRNA MALAT1 as a therapeutic target for the management of hypertension.

Mechanism of action of Profilin-1 and Fibulin-3 in vascular remodeling in hypertensive rats.

This paper aims to investigate the expressions of Fibulin-3 and Profilin-1 in vascular remodeling and the relationship between the two factors and vascular remodeling in hypertensive rats. 45 spontaneously hypertensive rats (SHR) and 15 healthy Wistar Kyoto (WKY) rats were collected. The 45 SHR were randomly divided into group A, group B, and group C. Group A was injected with Profilin-1 overexpression of adenoviral vector of pAd-Profilin-1-RES-EGFP; group B was injected with recombinant Fibulin3 protein solution; and group C was injected with normal saline. The rats in the control group were normally raised. All rats were anesthetized and dissected, and the thoracic aorta of rats was taken out at T0 (8 weeks old), T1 (12 weeks old), T2 (16 weeks old). The expressions of Fibulin-3 and Profilin-1 protein in the thoracic aorta were analyzed by Western blot. The overexpression of Profilin-1 and Fibulin-3 protein, blood pressure, and body weight were compared. The expression level and systolic blood pressure of Profilin-1 protein of rats in group A were significantly higher than those in the other two groups (p<0.05). The expression level of Fibulin-3 protein of rats in group B at T2 was significantly higher than that in the other two groups (p<0.05). The thickness of vascular wall in the control group and group C at T1 and T2 was significantly lower than that of group A and group B. The vascular wall/cavity ratio of rats in group A, B, C was significantly higher than that in the control group at T1 and T2 (p<0.001). The changes in Profilin-1 and Fibulin-3 levels may affect the occurrence and development of vascular remodeling in hypertension. Therefore, Profilin-1 and Fibulin-3 can be used as sensitive detection indices for hypertension vascular remodeling.

Impact of a Multichannel Blocker in Attenuating Intramyocardial Artery Remodeling in Hypertensive Rats through Increased Nitric Oxide Bioavailability.

Dronedarone is recommended for the treatment of atrial fibrillation. However, we do not know its effect on vascular remodeling. This study was designed to assess whether dronedarone has the potential to improve the intramyocardial artery remodeling induced by chronic hypertension. Ten-month-old male spontaneously hypertensive rats (SHR) were randomly assigned to receive dronedarone (100 mg/kg) or vehicle. Age-matched male Wistar-Kyoto rats served as controls. After 14 days of treatment, we studied the structure (geometry and fibrosis) of the intramyocardial artery using histological analysis. Nitric oxide (NO) in plasma was analyzed. In the untreated SHR, we observed a significant increase in external diameter, lumen diameter, wall width, cross-sectional area, and collagen volume density, as was expected in the experimental model. Dronedarone induced a significant decrease in wall width, cross-sectional area, and collagen volume density in SHR-D in comparison with untreated SHR. The values obtained in SHR-D were similar in the WKY control group. We found significantly higher NO levels in plasma in SHR-D than in untreated SHR. Dronedarone improves the intramyocardial artery remodeling induced by chronic hypertension in SHR through increased nitric oxide bioavailability.

Chronic treatment with C-type natriuretic peptide impacts differently in the aorta of normotensive and hypertensive rats.

The aim of this study was to determine whether exogenous administration of C-type natriuretic peptide (CNP) induces functional and morphological vascular changes in spontaneously hypertensive rats (SHR) compared with normotensive rats. Male 12-week-old normotensive Wistar and SHR were administered with saline (NaCl 0.9%) or CNP (0.75μg/h/100g) for 14days (subcutaneous micro-osmotic pumps). Systolic blood pressure (SBP) was measured in awake animals and renal parameters were evaluated. After decapitation, the aorta was removed, and vascular morphology, profibrotic markers, and vascular reactivity were measured. In addition, nitric oxide (NO) system and oxidative stress were evaluated. After 14-days of treatment, CNP effectively reduced SBP in SHR without changes in renal function. CNP attenuated vascular remodeling in hypertensive rats, diminishing both profibrotic and pro-inflammatory cytokines. Also, CNP activated the vascular NO system and exerted an antioxidant effect in aortic tissue of both groups, diminishing superoxide production and thiobarbituric acid-reactive substances, and increasing glutathione content. These results show that chronic treatment with CNP attenuates the vascular damage development in a model of essential hypertension, inducing changes in fibrotic, inflammatory, oxidative, and NO pathways that could contribute to beneficial long-term effects on vascular morphology, extracellular matrix composition, and function. The knowledge of these effects of CNP could lead to improved therapeutic strategies to not only control BP but also reduce vascular damage, primarily responsible for the risk of cardiovascular events.

GW27-e0997 Effect of NOD1/RIP2 signaling pathway on cardiovascular remodeling in hypertensive rats

The innate immune systems and its mediated inflammatory responses play a prominent role in the initiation and maintenance of hypertension and significantly contributes to target organ damage and mortality.NOD1 receptor is an innate immune pattern recognition receptor, and play an important role in

Oral administration of veratric acid, a constituent of vegetables and fruits, prevents cardiovascular remodelling in hypertensive rats: a functional evaluation.

In our previous studies, veratric acid (VA) shows beneficial effect on hypertension and its associated dyslipidaemia. In continuation, this study was designed to investigate the effect of VA, one of the major benzoic acid derivatives from vegetables and fruits, on cardiovascular remodelling in hypertensive rats, primarily assessed by functional studies using Langendorff isolated heart system and organ bath system. Hypertension was induced in male albino Wistar rats by oral administration of N ω -nitro-l-arginine methyl ester hydrochloride (l-NAME) (40 mg/kg body weight (b.w.)) in drinking water for 4 weeks. VA was orally administered at a dose of 40 mg/kg b.w. l-NAME-treated rats showed impaired cardiac ventricular and vascular function, evaluated by Langendorff isolated heart system and organ bath studies, respectively; a significant increase in the lipid peroxidation products such as thiobarbituric acid-reactive substances and lipid hydroperoxides in aorta; and a significant decrease in the activities of superoxide dismutase, catalase, glutathione peroxidase and levels of GSH, vitamin C and vitamin E in aorta. Fibrotic remodelling of the aorta and heart were assessed by Masson's Trichrome staining and Van Gieson's staining, respectively. In addition, l-NAME rats showed increased heart fibronectin expression assessed by immunohistochemical analysis. VA supplementation throughout the experimental period significantly normalised cardiovascular function, oxidative stress, antioxidant status and fibrotic remodelling of tissues. These results of the present study conclude that VA acts as a protective agent against hypertension-associated cardiovascular remodelling.

High intensity interval and endurance training have opposing effects on markers of heart failure and cardiac remodeling in hypertensive rats.

There has been re-emerging interest and significant work dedicated to investigating the metabolic effects of high intensity interval training (HIIT) in recent years. HIIT is considered to be a time efficient alternative to classic endurance training (ET) that elicits similar metabolic responses in skeletal muscle. However, there is a lack of information on the impact of HIIT on cardiac muscle in disease. Therefore, we determined the efficacy of ET and HIIT to alter cardiac muscle characteristics involved in the development of diastolic dysfunction, such as ventricular hypertrophy, fibrosis and angiogenesis, in a well-established rodent model of hypertension-induced heart failure before the development of overt heart failure. ET decreased left ventricle fibrosis by ~40% (P < 0.05), and promoted a 20% (P<0.05) increase in the left ventricular capillary/fibre ratio, an increase in endothelial nitric oxide synthase protein (P<0.05), and a decrease in hypoxia inducible factor 1 alpha protein content (P<0.05). In contrast, HIIT did not decrease existing fibrosis, and HIIT animals displayed a 20% increase in left ventricular mass (P<0.05) and a 20% decrease in cross sectional area (P<0.05). HIIT also increased brain natriuretic peptide by 50% (P<0.05), in the absence of concomitant angiogenesis, strongly suggesting pathological cardiac remodeling. The current data support the longstanding belief in the effectiveness of ET in hypertension. However, HIIT promoted a pathological adaptation in the left ventricle in the presence of hypertension, highlighting the need for further research on the widespread effects of HIIT in the presence of disease.

Heterogeneity in arterial remodeling among sublines of spontaneously hypertensive rats.

ObjectivesSpontaneously hypertensive rats (SHR) have been used frequently as a model for human essential hypertension. However, both the SHR and its normotensive control, the Wistar Kyoto rat (WKY), consist of genetically different sublines. We tested the hypothesis that the pathophysiology of vascular remodeling in hypertension differs among rat sublines.Methods and ResultsWe studied mesenteric resistance arteries of WKY and SHR from three different sources, at 6 weeks and 5 months of age. Sublines of WKY and SHR showed differences in blood pressure, body weight, vascular remodeling, endothelial function, and vessel ultrastructure. Common features in small mesenteric arteries from SHR were an increase in wall thickness, wall-to-lumen ratio, and internal elastic lamina thickness.ConclusionsEndothelial dysfunction, vascular stiffening, and inward remodeling of small mesenteric arteries are not common features of hypertension, but are subline-dependent. Differences in genetic background associate with different types of vascular remodeling in hypertensive rats.

Implementation and validation of aortic remodeling in hypertensive rats.

A computational framework was implemented and validated to better understand the hypertensive artery remodeling in both geometric dimensions and material properties. Integrating the stress-modulated remodeling equations into commercial finite element codes allows a better control and visualization of local mechanical parameters. Both arterial thickening and stiffening effects were captured and visualized. An adaptive material remodeling strategy combined with the element birth and death techniques for the geometrical growth were implemented. The numerically predicted remodeling results in terms of the wall thickness, inner diameter, and the ratio of elastin to collagen content of the artery were compared with and fine-tuned by the experimental data from a documented rat model. The influence of time constant on the material remodeling was also evaluated and discussed. In addition, the geometrical growth and material remodeling were isolated to better understand the contributions of each element to the arterial remodeling and their coupling effect. Finally, this framework was applied to an image-based 3D artery generated from computer tomography to demonstrate its heterogeneous remodeling process. Results suggested that hypertension induced arterial remodeling are quite heterogeneous due to both nonlinear geometry and material adaptation process. The developed computational model provided more insights into the evolutions of morphology and material of the artery, which could complement the discrete experimental data for improving the clinical management of hypertension. The proposed framework could also be extended to study other types of stress-driven tissue remodeling including in-stent restenosis and grafting.

Captopril treatment improves endothelium dependent dilation and middle cerebral artery remodeling in hypertensive rats (841.8)

Hypertension is associated with cognitive deficits. Angiotensin converting enzyme inhibitors (ACEI) improve cognitive decline in hypertensive patients. We hypothesized that centrally active ACEI captopril (CTP) would alleviate cognitive function by improving endothelium dependent dilation and middle cerebral artery (MCA) remodeling from stroke prone spontaneously hypertensive rats (SHRSP). Data are shown as mean±SEM, SHRSP vs CTP and are analyzed by Student’s t‐test. 12 week old male SHRSP received CTP (50 mg/kg/day) for 6 weeks. Cognitive function, evaluated by Morris water maze, showed no difference between groups. CTP reduced systolic blood pressure (178±8 vs 131±6 mmHg, p&lt;0.05). MCA reactivity and passive structure was assessed by pressure myography (data shown at 80 mmHg). CTP did not increase lumen diameter (232.6±8.1 vs 249.1±8.1). CTP reduced wall thickness (21.9±0.1 vs 17.3±1.0 µm, p&lt;0.05) and wall/lumen ratio (0.1±0.01 vs 0.07±0.01, p&lt;0.05). CTP improved endothelial function as evidenced by enhanced dilation to 10 µM adenosine diphosphate (change in diameter from baseline at: 36.2±1.0 vs 54.2± 5.3 µm, p&lt;0.05). CTP increased resting pial artery perfusion (673±32 vs 750±201 laser Doppler units, p&lt;0.05). These data suggests that while CTP does not affect cognitive abilities, it may contribute to increased baseline perfusion by enhancing dilation and reversing remodeling of MCAs.