Ventricle Weight Research Articles

Loss of Cardiac Muscle Ring Finger‐1 Augments Right Ventricular Hypertrophy Following Chronic Hypoxia‐Induced Pulmonary Hypertension

Exposure to chronic hypoxia (CH) induces elevated pulmonary artery pressure/resistance, leading to an eventual maladaptive right ventricular hypertrophy (RVH). Muscle RING‐finger (MuRF)1 is a muscle specific protein has been shown to play a role in left ventricular hypertrophy and altered cardiac bioenergetics in pressure overloaded hearts, however little is known about the contribution of MuRF1 impacting RVH in the setting of CH. Therefore, we hypothesized that MuRF1 deletion would enhance RVH compared to their wild‐type (WT) littermates following CH‐induced pulmonary hypertension. Thus, we assessed right ventricular systolic pressure (RVSP), right ventricle to left ventricle plus septal weight ratio (RV/LV+S) and hematocrit (Hct) following a 3 week isobaric CH exposure. CH induced pulmonary hypertension, measured by increases RVSP, RV/LV+S and Hct, WT mice compared to normoxic WT mice. Normoxic WT and MuRF1‐null mice exhibited no significant differences in RVSP, RV/LV+S or Hct. CH‐induced increases in RVSP were also similar between WT and MuRF1‐null mice; however, RV/LV+S and Hct were significantly elevated in CH‐exposed MuRF1‐null mice compared to WT. In conclusion, these results suggest an atrophic role for MuRF1 regulating the magnitude of right ventricular hypertrophy and polycythemia following CH‐induction of pulmonary hypertension.

Pentoxifylline reduces myocardial oxidative stress induced by exposure to tobacco smoke

The objective of this study is to evaluate the role of pentoxifylline (P) in heart remodeling induced by exposure to tobacco smoke (ETS).MethodsWistar rats were allocated in 4 groups: C (control); S (smoke); P (diet with P 100mg/kg) SP (smoke + diet with P100mg/kg). After 2 months, animals were submitted to echocardiography, isolated heart study, and oxidative stress evaluation. Two way anova and Holm Sidak tests were performed.ResultsETS leaded to an increase in left atrium area (p=0,04) and in left ventricle weight (p=0,04) and to impairment of ventricle function that was improved by pentoxifylline as observed in maximum positive derivative (C=3851±245; P=3500±400; S=2725±310; SP=3950± 310) (p=0,01). ETS increased oxidative stress that was attenuated by pentoxifylline: lipoperoxides (C=133,4±14,7; S=175,8±11,5; P=100,0±14,5; SP=128,3±11,9) (p<0,001), Glutathione peroxidases (C=37,4±4,8; S=17,519±3,9; P=33,6±6,4; SP=37,2±5,3) (p<0,001), superoxide dismutase (C=19,4±1,9; S=11,2±0,89; P=16,4±1,6; SP=21,7±2,9) (p<0,001).ConclusionIt is possible that pentoxifylline attenuates cardiac remodeling induced by ETS, in part due to reduction of oxidative stress.

Bosentan and Sildenafil reduce pulmonary arterial hypertension in rats induced by semaxanib and a low oxygen environment

Previous work has demonstrated the development of increased pulmonary artery pressures, hypertrophy of the pulmonary arterial vascular smooth muscle, and proliferation of the endothelial vascular lumen in rats following extended exposure to hypoxia and VEGF‐receptor antagonists. We validated this model of pulmonary arterial hypertension (PAH) by evaluating its utility as a clinically relevant paradigm to determine the efficacy of test articles against PAH. Male SD rats (240–370 g) were kept inside a hypoxic tent. Atmospheric oxygen was reduced to 13.5% using an oxygen scrubber. Rats received a single dose of semaxanib (200 mg/kg, s.c.) and were maintained inside the tent for 3 weeks. Rats received oral doses of vehicle (20% cyclodextrin, 10mL/kg once daily), bosentan (BS‐ 300mg/kg once daily) or sildenafil (SL‐ 30mg/kg twice daily). At day 21, pulmonary and systemic arterial pressures and thoracic organ weights were measured. BS and SL‐treated rats exhibited systolic, diastolic and mean pulmonary arterial pressures (21 and 19; 16 and 15; 18 and 17 mmHg, respectively) that were significantly lower compared to the vehicle (30, 22 and 26 mmHg, respectively). There was a trend toward decreased right ventricle to left ventricle weight ratio when comparing BS and SL with the vehicle. There were no significant differences in mean arterial pressure among rats treated with BS and SL as compared to vehicle. In summary, oral administration of BS and SL reduces PAH induced semaxanib and a low oxygen environment in a clinically relevant model.

Compensatory remodeling of coronary microvasculature maintains shear stress in porcine left-ventricular hypertrophy

Hypertension-induced left-ventricular hypertrophy (LVH) is generally accompanied with coronary neovascularization. The extent of vascular growth or rarefaction depends on many factors (e.g. age, duration of hypertension, degree of hypertrophy). Here, we hypothesize that there is a compensatory vascular growth that maintains uniform wall shear stress (WSS) in perfusion arterioles (diameters of 8-60 μm) in LVH of young porcine. To test this hypothesis, we investigated LVH in young porcine after 5 weeks of supravalvular aortic stenosis (3 months of age). The morphometry (diameters, lengths, number and connectivity of vessels) of the entire left circumflex (LCx) arterial tree was determined and a hemodynamic network analysis was used to calculate the distribution of pressure, flow and WSS throughout the tree in the control and LVH groups. It was found that the number of vessels and the weight of left ventricle (LV) in hypertrophy increased 1.5 and 1.2 times, respectively, and the length of the LCx main trunk increased by 3 cm (36% increase), as compared with those in control group. There were similar myocardial blood flows of 0.87 ± 0.24 and 0.94 ± 0.38 ml/min per g in control and LVH hearts, respectively. The compensatory remodeling in early LVH restores WSS in the smaller perfusion arterioles, but not in the larger epicardial branches. The present findings quantify the structural and functional remodeling in the entire LCx arterial tree in response to LVH, which reflect heterogeneity in vascular morphometry and hemodynamics from small to large vessels. These conclusions enhance our understanding of compensatory vascular remodeling in LVH of pediatric heart.

Antagonism of CXCR7 attenuates chronic hypoxia–induced pulmonary hypertension

Chemokines may directly participate in the pathogenesis of neonatal chronic hypoxia-induced pulmonary hypertension (PH). Although stromal-derived factor-1 (SDF-1) has been shown to be involved in PH, the role of its most recently discovered receptor, chemokine receptor type 7 (CXCR7), remains unclear. We sought to determine whether antagonism of the CXCR7 receptor would decrease pulmonary vascular remodeling in newborn mice exposed to chronic hypoxia by decreasing pulmonary vascular cell proliferation. Neonatal mice were exposed to hypoxia (fractional inspired oxygen concentration = 0.12) or room air (RA) for 2 wk. After 1 wk of exposure, mice received daily injections of placebo or a CXCR7 antagonist (CCX771) from postnatal day 7 (P7) to P14. Right ventricular systolic pressure (RVSP), the ratio of the weight of the right ventricle to left ventricle + septum (RV/LV + S), and pulmonary vascular cell proliferation and remodeling were determined at P14. As compared with mice exposed to RA, hypoxia placebo mice had a significant increase in the lung protein expression of CXCR7. Although hypoxic placebo-treated mice had a significant increase in RVSP, RV/LV+S, and pulmonary vascular cell proliferation and remodeling, the administration of CCX771 markedly decreased these changes. These results indicate that antagonism of CXCR7 may be a potent strategy to decrease PH and vascular remodeling.

Cardiac and Vascular Atrogin-1 mRNA Expression is Not Associated with Dexamethasone Efficacy in the Monocrotaline Model of Pulmonary Hypertension

Atrophic signaling elements of the ubiquitin-proteasome system (UPS) are involved in skeletal muscle wasting as well as pressure overload models of heart failure. In our prior experiments, we demonstrated a transcriptional downregulation of atrophy-inducing vascular E3 ubiquitin ligases in a toxic model of pulmonary hypertension where pulmonary artery and right ventricle (RV) hypertrophy are evident. Given the numerous reports of glucocorticoid activation of the UPS and the negative regulator of muscle mass, myostatin, we investigated the efficacy of dexamethasone to reverse monocrotaline (MCT)-induced pulmonary hypertension and augment atrogin-1 expression in both pulmonary arteries and myocardium. Dexamethasone caused significant reductions in body weight in combination with MCT. As predicted, MCT-induced pulmonary hypertension was evident by increases in RV systolic pressure, right ventricle to left ventricle plus septal weight ratios (RV/LVS) and arterial remodeling. MCT treatment significantly reduced both RV and PA atrogin-1 expression. Dexamethasone treatment reversed the MCT-induced pathological indices and restored RV atrogin-1 expression, but did not impact atrogin-1 expression in pulmonary arteries. Myostatin was poorly expressed in pulmonary arteries compared to the RV, and dexamethasone treatment increase RV myostatin in controls but not MCT-treated rats. These findings suggest that mechanisms independent of myostatin/atrogin-1 are responsible for glucocorticoid efficacy in this model of pulmonary hypertension.

Comparação de dois modelos experimentais de hipertensão pulmonar

To compare two models of pulmonary hypertension (monocrotaline and monocrotaline+pneumonectomy) regarding hemodynamic severity, structure of pulmonary arteries, inflammatory markers (IL-1 and PDGF), and 45-day survival. We used 80 Sprague-Dawley rats in two study protocols: structural analysis; and survival analysis. The rats were divided into four groups: control; monocrotaline (M), pneumonectomy (P), and monocrotaline+pneumonectomy (M+P). In the structural analysis protocol, 40 rats (10/group) were catheterized for the determination of hemodynamic variables, followed by euthanasia for the removal of heart and lung tissue. The right ventricle (RV) was dissected from the interventricular septum (IS), and the ratio between RV weight and the weight of the left ventricle (LV) plus IS (RV/LV+IS) was taken as the index of RV hypertrophy. In lung tissues, we performed histological analyses, as well as using ELISA to determine IL-1 and PDGF levels. In the survival protocol, 40 animals (10/group) were followed for 45 days. The M and M+P rats developed pulmonary hypertension, whereas the control and P rats did not. The RV/LV+IS ratio was significantly higher in M+P rats than in M rats, as well as being significantly higher in M and M+P rats than in control and P rats. There were no significant differences between the M and M+P rats regarding the area of the medial layer of the pulmonary arteries; IL-1 and PDGF levels; or survival. On the basis of our results, we cannot conclude that the monocrotaline+pneumonectomy model is superior to the monocrotaline model.

Estimated RV/TV Based on Empirical Mode Decomposition of Heart Sound

In the poultry industry we have problems like Ascites and SDS (Sudden Death Syndrome) that they are dependent on weak vascular system. Analysis of the heart sounds could be a way to estimate the heart's strength. Estimating the heart strength with the RV/TV (ratio of the right ventricle weight to total heart weight) index, could help to diagnose chickens with low RV/TV in high genetic stocks (Broiler Breeders) and decline these problems in the next generations. In this paper, we applied the EMD method for decomposition of the chicken heart sounds to compare their RV/TV. We have chosen to use the global maxima of 5 th IMF as extracted feature. The results presented a linear relationship between extracted features of the chicken heart sounds and RV/TV ratios.

Effects of kimchi supplementation on blood pressure and cardiac hypertrophy with varying sodium content in spontaneously hypertensive rats

We tested the effects of dietary intake of freeze-dried Korean traditional fermented cabbage (generally known as kimchi) with varying amounts of sodium on blood pressure and cardiac hypertrophy in spontaneously hypertensive rats (SHRs). Wistar-Kyoto rats (WKY), as a control group, received a regular AIN-76 diet, and the SHRs were divided into four groups. The SHR group was fed a regular diet without kimchi supplementation, the SHR-L group was fed the regular diet supplemented with low sodium kimchi containing 1.4% salt by wet weight, which was provided in a freeze-dried form, the SHR-M group was supplemented with medium levels of sodium kimchi containing 2.4% salt, and the SHR-H group was supplemented with high sodium kimchi containing 3.0% salt. Blood pressure was measured over 6 weeks, and cardiac hypertrophy was examined by measuring heart and left ventricle weights and cardiac histology. SHRs showed higher blood pressure compared to that in WKY rats, which was further elevated by consuming high sodium containing kimchi but was not influenced by supplementing with low sodium kimchi. None of the SHR groups showed significant differences in cardiac and left ventricular mass or cardiomyocyte size. Levels of serum biochemical parameters, including blood urea nitrogen, creatinine, glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, sodium, and potassium were not different among the groups. Elevations in serum levels of aldosterone in SHR rats decreased in the low sodium kimchi group. These results suggest that consuming low sodium kimchi may not adversely affect blood pressure and cardiac function even under a hypertensive condition.

Abstract 9178: Cell-Based Prostacyclin Gene Therapy Prevents Pulmonary Arterial Hypertension

Objectives: Intravenous prostacyclin is approved for the treatment of pulmonary arterial hypertension (PAH). However, it has limitations of a short half-life, the permanent placement of an intravenous catheter and substantial annual cost. We hypothesized that cell-based prostacyclin gene therapy may provide sustained therapeutic effects without the aforementioned limitations. Methods and Results: Since prostacyclin is produced from arachidonic acid by the enzymes cyclooxygenase (COX) and prostacyclin synthase (PGIS), we generated a vector expressing COX isoform 1 (COX1) and PGIS fusion protein that is capable of producing prostacyclin from arachidonic acid. Endothelium-like progenitor cells (ELPCs) from syngenetic Fisher 344 rats were transfected with COX1-PGIS expressing vector and lentivirus expressing nuclear localized red fluorescent protein (nuRFP). The engineered ELPCs expressing COX1-PGIS and nuRFP were tested in a monocrotaline (MCT) induced rat PAH model. Twenty-five days after cell transplantation, 48% of transplanted ELPCs resided in the lungs. MCT induced an increase in right ventricular systolic pressure (RVSP) compared to normal controls (51.9 ±2.2 mmHg vs. 26.3 ± 1.5 mmHg, p<0.01). The increase in RVSP was significantly attenuated by treatment with ELPCs alone (40.9 ±1.6 mmHg, p<0.01) or with ELPCs engineered to express the COX1-PGIS transgene (35.9 ±1.6 mmHg, p<0.01). Engineered ELPCs were significantly more effective than ELPCs alone in preventing the increase in RVSP (p<0.05). Right ventricle hypertrophy (right ventricle vs. left ventricle plus septum weight ratio) was reduced by treatment with ELPCs (28.8±0.8% vs. 36.5±3.1%, p <0.01) or engineered ELPCs (30.5±0.9% vs. 36.5±3.1%, p <0.01). Lung vessel thickness index increase (reflecting intima thickening and medial smooth muscle hypertrophy) was attenuated by treatment with engineered ELPCs (78.1±3.1% vs. 90.1±4.1%, p <0.05). Conclusions: COX1-PGIS expressing ELPCs prevented MCT-induced PAH and showed enhanced efficacy over ELPCs alone. The one time cell delivery offered sustained therapeutic efficacy for at least 25 days, which may provide a promising option for patients with PAH.

Relaxin and Castration in Male Mice Protect from, but Testosterone Exacerbates, Age-Related Cardiac and Renal Fibrosis, Whereas Estrogens Are an Independent Determinant of Organ Size

This study determined the effects of castration and hormone replacement therapy on the age-related cardiac and renal pathology of male relaxin gene-knockout (RlnKO) and age-matched wild-type (RlnWT) mice and that of aged male aromatase knockout (ArKO) mice, which lack estrogens and have 5-10 times the androgen levels of male wild-type mice. One-month-old RlnWT and RlnKO mice were bilaterally gonadectomized or sham operated and maintained until 12 months. Subgroups of castrated animals received testosterone or 17β-estradiol treatment from 9 to 12 months. Male ArKO mice and aromatase wild-type mice were aged to 12 months. Collected heart and kidney tissues were assessed for changes in organ size and fibrosis. Castration reduced body, heart, left ventricle, and kidney weights in both RlnKO and RlnWT mice, and the cardiac/renal fibrosis that was seen in sham RlnKO animals (all P < 0.05 vs. respective sham). Testosterone normalized organ weights and organ weight to body weight ratio of castrated animals and increased cardiac/renal collagen concentration to levels measured in or beyond that of sham RlnKO mice (all P < 0.05 vs. respective castrated mice). Furthermore, expression of TGF-β1, mothers against decapentaplegic homolog 2 (Smad2), and myofibroblast differentiation paralleled the above changes (all P < 0.05 vs. respective castrated mice), whereas matrix metalloproteinase-13 was decreased in testosterone-treated RlnKO mice. Conversely, 17β-estradiol only restored changes in organ size. Consistent with these findings, intact ArKO mice demonstrated increased cardiac/renal fibrosis in the absence of changes in organ size. These findings suggest that relaxin and castration protect, whereas androgens exacerbate, cardiac and renal fibrosis during ageing, whereas estrogens, in synergy with relaxin, regulates age-related changes in organ size.

Fetal growth restriction and the programming of heart growth and cardiac insulin‐like growth factor 2 expression in the lamb

Reduced growth in fetal life together with accelerated growth in childhood, results in a ~50% greater risk of coronary heart disease in adult life. It is unclear why changes in patterns of body and heart growth in early life can lead to an increased risk of cardiovascular disease in adulthood. We aimed to investigate the role of the insulin-like growth factors in heart growth in the growth-restricted fetus and lamb. Hearts were collected from control and placentally restricted (PR) fetuses at 137-144 days gestation and from average (ABW) and low (LBW) birth weight lambs at 21 days of age. We quantified cardiac mRNA expression of IGF-1, IGF-2 and their receptors, IGF-1R and IGF-2R, using real-time RT-PCR and protein expression of IGF-1R and IGF-2R using Western blotting. Combined bisulphite restriction analysis was used to assess DNA methylation in the differentially methylated region (DMR) of the IGF-2/H19 locus and of the IGF-2R gene. In PR fetal sheep, IGF-2, IGF-1R and IGF-2R mRNA expression was increased in the heart compared to controls. LBW lambs had a greater left ventricle weight relative to body weight as well as increased IGF-2 and IGF-2R mRNA expression in the heart, when compared to ABW lambs. No changes in the percentage of methylation of the DMRs of IGF-2/H19 or IGF-2R were found between PR and LBW when compared to their respective controls. In conclusion, a programmed increased in cardiac gene expression of IGF-2 and IGF-2R may represent an adaptive response to reduced substrate supply (e.g. glucose and/or oxygen) in order to maintain heart growth and may be the underlying cause for increased ventricular hypertrophy and the associated susceptibility of cardiomyocytes to ischaemic damage later in life.

The role of oxidative stress in the development of congestive heart failure (CHF) in broilers with pulmonary hypertension syndrome (PHS)

The present study examined the possible role of reactive oxygen species in the pathogenesis of heart failure in broilers. Our experiment was conducted with 160 one–day-old male broilers (Ross 308) to investigate the mechanisms of cell injury in the pathogenesis of pulmonary hypertension syndrome. The chickens were divided into two groups of four replicates each, with 20 chicks per replicate. One group was raised in normal temperature (NT) while the other group was raised in cold temperature (CT) to induce the pulmonary hypertension syndrome. Mortality was inspected to determine cause of death and diagnose heart failure. Hematological, biochemical and pathological tests were used to determine the incidence of PHS: total red blood cell (RBC), hemoglobin (HGB), hematocrit (HCT), activity of alanine transaminase (ALT), aspartate transaminase (AST) and lactate dehydrogenase (LDH). Malondialdehyde (MDA) was used as an indicator of lipid oxidation, subsequent to generated oxidative stress. Samples of blood and liver tissue were taken at day 21 and 42 of age. At the end of the experiment (week 6), 2 chicks from each replicate were randomly selected and slaughtered. The heart was removed, the right ventricle was dissected away from the left ventricle and septum, and the ratio of right ventricle weight to total ventricle weight (RV/TV) was calculated. The results of our experiment indicated the significant difference between the two groups for RBC and HGB and for RBC, HGB and HCT at days 21 and 42 of age, respectively. However, there was no significant difference for activity of ALT, AST and LDH in plasma between the groups at day 21 of age. but CT birds had higher levels (p < 0.05) AST, ALT and LDH activities in plasma as compared with other birds. MDA content of plasma and liver was significantly higher (p < 0.05) in CT group at both ages. RV/TV ratio and mortality due to ascites were significantly higher in CT birds. In conclusion, heart failure and subsequent PHS can be associated with oxidative stress. Key words: Oxidative stress, heart failure, ascites, hematological, broiler.

Overexpression of thioredoxin 2 does not affect hypoxia‐induced right ventricular hypertrophy

Pulmonary hypertension (PH) is characterized by increased pulmonary vascular resistance and vasoconstriction that can result in right ventricular hypertrophy. Studies suggest that mitochondrial reactive oxygen species (ROS) may play a role in right ventricular hypertrophy and PH pathogenesis. The present study examines the effects of overexpression of Thioredoxin 2 (Trx2), a mitochondrial ROS scavenger, in the development of hypoxia-induced right ventricular hypertrophy. Western blot analysis was used to confirm Trx2 overexpression in transgenic mice. Wild-type (WT) and Trx2 transgenic (Tg) mice were exposed to normoxic or hypoxic conditions for three weeks. Blood was collected for hematocrit measurement and hearts removed to assess right ventricular hypertrophy using right ventricle/left ventricle plus septum (RV/LV+S) weight ratios. Trx2 Tg mice have increased Trx2 expression in the lung. Hypoxia exposure significantly elevated hematocrit in both WT and Trx2 Tg mice relative to normoxic animals (p<0.05). Similarly, hypoxia increased RV/LV+S weight ratios for WT and Trx2 Tg mice when compared to WT normoxic conditions (p<0.05). These results suggest that increased expression of Trx2 in pulmonary tissue does not affect the progression of hypoxia-induced right ventricular hypertrophy. Funding by: VA Research Service Award DK074518 and Toxicology Training Grant 5T32ES012870-07.

Acriflavine Attenuates the Development of Hypoxic Pulmonary Hypertension

Hypoxia Inducible Factor (HIF) is a highly conserved, heterodimeric transcription factor that has been shown to mediate the development of hypoxia pulmonary hypertension (HPH). Previous studies have identified acriflavine as a drug that binds directly to the PAS-B domain of HIF-1α and HIF-2 α inhibiting dimerization. Therefore, we hypothesized that treatment with acriflavine could reduce the development of HPH. In this study, adult male Wistar rats were weighed daily and injected with 2 mg/kg of acriflavine or saline, while being housed in either room air or in a chamber flushed with a mix of air and nitrogen to achieve 10% O2. After 21 days, we measured right ventricular pressure (RVP) via closed chest cardiac puncture, right ventricle and left ventricle plus septum weights and hematocrit (HCT). Pulmonary arterial smooth muscle cells were isolated from intrapulmonary arteries and used for measurement of intracellular calcium concentration [Ca2+]i using Fura-2 AM. In saline treated animals, chronic hypoxia lead to increased RVP, right ventricle hypertrophy, HCT, and [Ca2+]i. All of these variables were significantly reduced in chronically hypoxic animals receiving acriflavine. These results indicate that acriflavine attenuates the development of HPH.

High eggshell temperatures during incubation decrease growth performance and increase the incidence of ascites in broiler chickens

High eggshell temperatures (EST; ≥38.9°C) during the second half of incubation are known to decrease the body and organ development of broiler hatchlings. In particular, relative heart weights are decreased by a high EST, and this may increase the incidence of metabolic disorders that are associated with cardiovascular development, such as ascites. The current study investigated the effects of a high EST on chick quality, subsequent performance, and the incidence of ascites later in life. Eggs were incubated at a normal (37.8°C) or high (38.9°C) EST from d 7 of incubation onward. After hatching, the chickens were housed per EST in pens, and a normal or cold temperature schedule was applied during the grow-out period. Hatchability, hatchling quality, BW, feed conversion ratio, total mortality, mortality associated with ascites, slaughter characteristics, and ascites susceptibility at 6 wk of age were evaluated. Except for total ventricle weight, no interaction was found between EST and the grow-out temperature. Hatchability was comparable between the EST treatments, but the percentage of second-grade chickens was 0.7% higher at the high EST. Yolk-free body mass was 3.0 g lower, and heart weights were 26% lower at hatch in the high compared with the normal EST treatment. Body weight continued to be less during the grow-out period after the high EST incubation. However, breast meat yield was 1.0% higher in the high than in the normal EST. Feed conversion ratio did not differ between EST treatments. Total mortality was 4.1% higher and mortality associated with ascites was 3.8% higher in the high compared with the normal EST treatment. The ratio between the right and total ventricle was 1.1% higher in the high compared with the normal EST treatment at slaughter age. In conclusion, a high EST from d 7 of incubation onward decreased hatchling quality and growth performance, but increased breast meat yield. Furthermore, high EST incubation increased the incidence of ascites, which may be related to the reduced heart development at hatch.

P53 Gene deficiency promotes hypoxia-induced pulmonary hypertension and vascular remodeling in mice

Chronic hypoxia induces pulmonary arterial remodeling, resulting in pulmonary hypertension and right ventricular hypertrophy. Hypoxia has been implicated as a physiological stimulus for p53 induction and hypoxia-inducible factor-1α (HIF-1α). However, the subcellular interactions between hypoxic exposure and expression of p53 and HIF-1α remain unclear. To examine the role of p53 and HIF-1α expression on hypoxia-induced pulmonary arterial remodeling, wild-type (WT) and p53 knockout (p53KO) mice were exposed to either normoxia or hypoxia for 8 wk. Following chronic hypoxia, both genotypes demonstrated elevated right ventricular pressures, right ventricular hypertrophy as measured by the ratio of the right ventricle to the left ventricle plus septum weights, and vascular remodeling. However, the right ventricular systolic pressures, the ratio of the right ventricle to the left ventricle plus septum weights, and the medial wall thickness of small vessels were significantly greater in the p53KO mice than in the WT mice. The p53KO mice had lower levels of p21 and miR34a expression, and higher levels of HIF-1α, VEGF, and PDGF expression than WT mice following chronic hypoxic exposure. This was associated with a higher proliferating cell nuclear antigen expression of pulmonary artery in p53KO mice. We conclude that p53 plays a critical role in the mitigation of hypoxia-induced small pulmonary arterial remodeling. By interacting with p21 and HIF-1α, p53 may suppress hypoxic pulmonary arterial remodeling and pulmonary arterial smooth muscle cell proliferation under hypoxia.

Combined effects of irbesartan and carvedilol on expression of tissue factor and tissue factor pathway inhibitor in rats after myocardial infarction

The objective of this study was to investigate the effects of irbesartan, carvedilol, and irbesartan plus carvedilol on the expression of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) mRNA and protein in rat myocardium after myocardial infarction (MI). MI was induced in male Wistar rats by ligation of the anterior descending branch of the left coronary artery. Irbesartan at 50mg/kg/day, carvedilol at 1mg/kg/day, irbesartan plus carvedilol, or placebo was administered intragastrically; expression of TF and TFPI mRNA and protein was determined by RT-PCR and Western blot analysis. The relative left ventricle weights were lower in all three treatment groups than in the placebo group, with the lowest relative weight in the irbesartan plus carvedilol group (P<0.001). The size of the infarcted area was lower in the carvedilol and the combined groups than in the placebo group (P<0.001). The levels of expression of TF and TFPI mRNA and protein were lower in the combined group than in the placebo group or the carvedilol group (P<0.001). Treatment with irbesartan plus carvedilol reduced the expression of TF and TFPI mRNA and protein after MI in rats, and combined treatment with both agents had greater effects than the single agents alone. These findings suggest that the beneficial effects of these drugs may include anticoagulation and that combined therapy with both agents is an option that should be evaluated further.

Recovery from Hypoxic Pulmonary Hypertension in Rats

To characterize the time frame of changes in pulmonary arterial pressure, right ventricular hypertrophy and morphology of small pulmonary arteries male Wistar rats were exposed to isobaric hypoxia (3 weeks, F1O2 0.1) and then let to recover on air for 1 or 5 weeks. Normoxic animals (group N) served as controls. Mean pulmonary arterial pressure (PAP), ratio of the weight of the right heart ventricle to the sum of the weights of the left ventricle and septum (RV/LV+S) and percentage of double laminated pulmonary vessels ( % DL) were measured at the end of hypoxic exposure (group H), after 1 or 5 weeks of recovery (groups 1R and 5R), and in controls kept in air (group N). Three weeks in hypoxia resulted in increase in PAP, RV/LV+S and % DL. After 1 week of recovery RV/LV+S normalized, PAP decreased, while % DL did not change. After 5 weeks in air PAP returned to control values and % DL diminished significantly but did not normalize. Our results suggest that recovery depends on the degree of HPH and that knowledge of the time-frame of recovery is important for future studies in our rat model.

Angiotensin-Converting Enzyme and Angiotensin-Converting Enzyme 2 Are Involved in Sinoaortic Denervation-Induced Cardiovascular Hypertrophy in Rats

The balance of angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) in high blood pressure variability (BPV) induced cardiovascular hypertrophy remains elusive. The aim of the present work was to investigate expression and activity of ACE and ACE2 in the heart and aorta of sinoaortic denervation (SAD) rats with high BPV and normal BP, and explore the potential role of ACE and ACE2 in high BPV-induced cardiovascular damage. Hemodynamics, cardiovascular hypertrophy, angiotensin II (Ang II) concentrations, ACE and ACE2 activity were determined. Cardiac-tissue ACE and ACE2 expression were assayed by real-time polymerase chain reaction and Western blot. Compared with sham-operated rats, systolic BPV and diastolic BPV increased and baroreflex sensitivity decreased significantly in SAD rats. SAD rats presented with obvious cardiovascular hypertrophy characterized by increased ratio of left ventricle weight to body weight and aortic weight to the length of aorta. There was no difference in plasma Ang II concentration between sham-operated and SAD rats. The cardiac and aortic ACE expression, aortic ACE2 expression and ACE activity were elevated in SAD rats. There was no significant difference in cardiac ACE2 expressions between sham-operated and SAD rats. The present work demonstrated that cardiac and aortic ACE expression, aortic ACE2 expression and ACE activity were increased in SAD rats. It is the tissue rather than the circulating renin-angiotensin system that contributes to high BPV-induced cardiovascular hypertrophy.