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1.
Genes (Basel) ; 14(1)2023 01 01.
Article in English | MEDLINE | ID: mdl-36672863

ABSTRACT

To explore the impact of omecamtiv mecarbil (OM) on the gene expression profile in adult male rats. Fourteen male Wistar rats were randomly assigned to a single OM (1.2 mg/kg/h; n = 6) or placebo (n = 8) 30-min infusion. Echocardiography was performed before and after OM infusion. Seven days after infusion, rats were euthanized, and left ventricular (LV) tissues were removed for real-time quantitative polymerase chain reaction (RTq-PCR) experiments. After OM infusion, pro-apoptotic Bax-to-Bcl2 ratio was decreased, with increased Bcl2 and similar Bax gene expression. The gene expression of molecules regulating oxidative stress, including glutathione disulfide reductase (Gsr) and superoxide dismutases (Sod1/Sod2), remained unchanged, whereas the expression of antioxidant glutathione peroxidase (Gpx) increased. While LV gene expression of key energy sensors, peroxisome proliferator activator (Ppar) α and γ, AMP-activated protein kinase (Ampk), and carnitine palmitoyltransferase 1 (Cpt1) remained unchanged after OM infusion, and the expression of pyruvate dehydrogenase kinase 4 (Pdk4) increased. The LV expression of the major myocardial glucose transporter Glut1 decreased, with no changes in Glut4 expression, whereas the LV expression of oxidized low-density lipoprotein receptor 1 (Olr1) and arachidonate 15-lipoxygenase (Alox15) increased, with no changes in fatty acid transporter Cd36. An increased LV expression of angiotensin II receptors AT1 and AT2 was observed, with no changes in angiotensin I-converting enzyme expression. The Kalikrein-bradykinin system was upregulated with increased LV expression of kallikrein-related peptidases Klk8, Klk1c2, and Klk1c12 and bradykinin receptors B1 and B2 (Bdkrb1 and Bdkrb2), whereas the LV expression of inducible nitric oxide synthase 2 (Nos2) increased. LV expression in major molecular determinants involved in calcium-dependent myocardial contraction remained unchanged, except for an increased LV expression of calcium/calmodulin-dependent protein kinase II delta (Cacna1c) in response to OM. A single intravenous infusion of OM, in adult healthy rats, resulted in significant changes in the LV expression of genes regulating apoptosis, oxidative stress, metabolism, and cardiac contractility.


Subject(s)
Calcium , Myosins , Rats , Male , Animals , Calcium/metabolism , bcl-2-Associated X Protein/metabolism , Rats, Wistar , Myosins/metabolism , Gene Expression , Calcium Channels, L-Type , Serine Endopeptidases/metabolism
2.
Arch Physiol Biochem ; 129(1): 222-232, 2023 Feb.
Article in English | MEDLINE | ID: mdl-32886530

ABSTRACT

CONTEXT: Metabolic syndrome (MetS) is a clustering of several physiological alterations. OBJECTIVE: This study was designed to evaluate the effects of MetS on rats spermatogenesis and steroidogenesis. MATERIALS AND METHODS: We developed a MetS rodent model using high-sugar and high-fat diet. RESULTS: MetS rats showed severe disorders in sperm parameters. Interestingly, a significant increase in malondialdehyde level and a decrease in the antioxidant activities were observed. Moreover, qRT-PCR analysis showed Bax down-regulation and Bcl-2 up-regulation. A decrease in testosterone level was identified, correlated with the CYP11A1, CYP17A1 and 17ß HSD testicular marker down-regulation. Finally, MetS rats showed an up-regulation of pro-inflammatory cytokines receptors IL-1R and IL-6R. CONCLUSION: MetS induced severe testis toxicity in male rats. Mets markedly distorted sperm parameters, inhibited the transcription of steroidogenic enzymes and led to oxidative stress, inflammation, and alteration of Bax/Bcl-2 ratioin testicular tissues.


Subject(s)
Metabolic Syndrome , Rats , Male , Animals , Metabolic Syndrome/metabolism , bcl-2-Associated X Protein/metabolism , Semen , Spermatogenesis , Testis , Oxidative Stress , Testosterone/metabolism
3.
J Basic Clin Physiol Pharmacol ; 33(6): 743-750, 2022 Nov 01.
Article in English | MEDLINE | ID: mdl-36215707

ABSTRACT

OBJECTIVES: Both N-terminal fragment of B-type natriuretic peptide (NT-proBNP) and soluble isoform of ST2 (sST2) have been identified as biomarkers of heart failure. We evaluated the plasma levels of NT-proBNP and sST2 in a rat model of severe aortic valve regurgitation (AR) and correlated these findings with echocardiographic measurements. We also examined the impact of omecamtiv mecarbil (OM) on these parameters. METHODS: The plasma levels of NT-proBNP and sST2 were measured in 18 rats both before and 2 months after surgical induction of AR, and at these same time points, in six rats assigned to a sham-procedure control group. Plasma biomarkers were then measured again after infusion of OM or placebo in rats with AR (n=8 and 10, respectively) and OM alone in the sham control rats (n=6). Echocardiographic measurements were collected before and 2 months after induction of AR. RESULTS: Our results revealed increased levels of plasma NT-proBNP (219 ± 34 pg/mL vs. 429 ± 374 pg/mL; p<0.001) in rats with AR at day 7 after infusion of placebo, whereas plasma levels of sST2 were higher in this cohort after infusion of either OM or placebo. We identified a significant positive correlation between plasma sST2 with posterior wall thickness in diastole (r=0.34, p<0.05) and total body weight (r=0.45, p<0.01) in rats with surgically induced AR. CONCLUSIONS: Because sST2 increased markedly, whereas NT-proBNP remained unchanged, when OM was administered, we hypothesize that sST2 has a distinct capability to detect deleterious effects of passive muscle tension, not reliably assessed by NT-proBNP, in the setting of AR.


Subject(s)
Aortic Valve Insufficiency , Natriuretic Peptide, Brain , Animals , Rats , Aortic Valve Insufficiency/drug therapy , Biomarkers
4.
Front Vet Sci ; 8: 732133, 2021.
Article in English | MEDLINE | ID: mdl-34631858

ABSTRACT

West Highland white terriers (WHWTs) affected with canine idiopathic pulmonary fibrosis (CIPF) are at risk of developing precapillary pulmonary hypertension (PH). In humans, thoracic computed tomography angiography (CTA) is commonly used to diagnose and monitor patients with lower airway diseases. In such patients, CTA helps to identify comorbidities, such as PH, that could negatively impact prognosis. Diameter of the pulmonary trunk (PT), pulmonary trunk-to-aorta ratio (PT/Ao), and right ventricle-to-left ventricle ratio (RV/LV) are CTA parameters commonly used to assess the presence of PH. Pulmonary vein-to-right pulmonary artery ratio (PV/PA) is a new echocardiographic parameter that can be used in dogs to diagnose PH. The primary aim of this study was to evaluate the use of various CTA parameters to diagnose PH. An additional aim was to evaluate the correlation of RV/LV measurements between different CTA planes. CTA and echocardiography were prospectively performed on a total of 47 WHWTs; 22 affected with CIPF and 25 presumed healthy control dogs. Dogs were considered to have PH if pulmonary vein-to-right pulmonary artery ratio (PV/PA) measured on 2D-mode echocardiography was less than to 0.7. WHWTs affected with CIPF had higher PT/Ao compared with control patients. In WHWTs affected with CIPF, PT size was larger in dogs with PH (15.4 mm) compared with dogs without PH (13 mm, p = 0.003). A cutoff value of 13.8 mm predicted PH in WHWTs affected with CIPF with a sensitivity of 90% and a specificity of 87% (AUC = 0.93). High correlations were observed between the different CTA planes of RV/LV. Results suggest that diameter of the PT measured by CTA can be used to diagnose PH in WHWTs with CIPF.

5.
Physiol Rep ; 9(16): e14988, 2021 08.
Article in English | MEDLINE | ID: mdl-34405966

ABSTRACT

In patients with chronic aortic regurgitation (AR), excessive preload and afterload increase left ventricle wall stress, leading to left ventricular systolic dysfunction. Thus, the objective of the present study was to evaluate the effects of the myosin activator omecamtiv mecarbil (OM) on left ventricle wall stress in an experimental rat model of severe chronic AR. Forty adult male Wistar rats were randomized into two experimental groups: induction of AR (acute phase) by retrograde puncture (n = 34) or a sham intervention (n = 6). Rats that survived the acute phase (n = 18) were randomized into an OM group (n = 8) or a placebo group (n = 10). Equal volumes of OM (1.2 mg/kg/h) or placebo (0.9% NaCl) were continuously infused into the femoral vein over 30 min. OM significantly decreased end-systolic and end-diastolic and maximum wall stress in this experimental rat model of chronic severe AR (p < 0.001) and increased systolic performance assessed by fractional shortening and left ventricle end-systolic diameter; both p < 0.05). These effects were correlated with decreased indices of global cardiac function (cardiac output and stroke volume; p < 0.05) but were not inferior to baseline pump indices. Infusion with placebo did not affect global cardiac function but decreased end-systolic wall stress (p < 0.05) and increased systolic performance (all p < 0.001). In the sham-operated (control) group, OM decreased diastolic wall stress (p < 0.05). Based on these results, OM had a favorable effect on left ventricle wall stress in an experimental rat model of severe chronic AR.


Subject(s)
Aortic Valve Insufficiency/drug therapy , Cardiotonic Agents/therapeutic use , Urea/analogs & derivatives , Animals , Cardiotonic Agents/administration & dosage , Cardiotonic Agents/pharmacology , Heart Ventricles/drug effects , Heart Ventricles/physiopathology , Infusions, Intravenous , Male , Rats , Rats, Wistar , Stroke Volume , Systole , Urea/administration & dosage , Urea/pharmacology , Urea/therapeutic use
6.
BMC Vet Res ; 17(1): 171, 2021 Apr 23.
Article in English | MEDLINE | ID: mdl-33892687

ABSTRACT

BACKGROUND: Pulmonary hypertension (PH) is a known co-morbidity in West Highland white terriers (WHWTs) affected with canine idiopathic pulmonary fibrosis (CIPF). The pulmonary vein-to-right pulmonary artery ratio (PV/PA) has recently been described for the detection of pre-capillary PH in dogs. The objective of the present study was to estimate the prevalence of PH at diagnostic, in WHWTs affected with CIPF, by using PV/PA, in comparison with a group of healthy breed-matched controls (CTRLs). Additional study objective was to explore whether the presence of PH at initial diagnosis of CIPF impacted survival time in dogs treated with sildenafil. RESULTS: Twenty-five client-owned WHWTs presented with CIPF and 19 CTRLs were included in the study. PV/PA in either two-dimensional mode (2D) or time-motion mode or both were measured from cineloops in each dog. Dogs were classified according to PV/PA value into non/mild PH (PV/PA measured in 2D ≥ 0.7) or moderate/severe PH (PV/PA < 0.7). Survival data of WHWTs affected with CIPF were extracted from medical record to assess association between presence of PH at diagnosis and outcome. 60 % overall prevalence for moderate/severe PH was estimated in this cohort of WHWTs presented with CIPF vs. 5 % in CTRLS (P = 0.0002). The presence of moderate/severe PH at initial presentation was not associated with survival. CONCLUSIONS: Results of the present study confirm a high prevalence of PH at diagnosis in WHWTs affected with CIPF and highlight the utility of PV/PA as a non-invasive surrogate for assessment of PH in this population.


Subject(s)
Dog Diseases/diagnostic imaging , Hypertension, Pulmonary/veterinary , Idiopathic Pulmonary Fibrosis/veterinary , Animals , Case-Control Studies , Dog Diseases/drug therapy , Dogs , Echocardiography/veterinary , Genetic Predisposition to Disease , Hypertension, Pulmonary/diagnostic imaging , Hypertension, Pulmonary/drug therapy , Prevalence , Pulmonary Artery/diagnostic imaging , Pulmonary Veins/diagnostic imaging , Sildenafil Citrate/therapeutic use , Treatment Outcome , Vasodilator Agents/therapeutic use
7.
Exp Physiol ; 106(5): 1249-1262, 2021 05.
Article in English | MEDLINE | ID: mdl-33660345

ABSTRACT

NEW FINDINGS: What is the central question of this study? The beneficial effects of supplemental oxygen in patients with acute myocardial infarction are still uncertain: what are the effects of ischaemia-reperfusion injury during hyperoxia and normoxia in mature rats with and without cardiovascular risk factors? What is the main finding and its importance? Despite elevated baseline oxidative stress in rodents with cardiovascular risk factors, hyperoxic reperfusion limited myocardial necrosis and anti/pro-oxidant imbalance in spontaneously hypertensive and Zucker rats. In contrast, this effect was exacerbated in healthy Wistar rats. These results suggest that oxygen supplementation may not be harmful in patients with acute myocardial injury. ABSTRACT: Recent studies on O2 supplementation in acute coronary syndrome patients are equivocal. We tested the hypothesis that oxidative stress is increased in rodents with cardiovascular risk factors and enhances ischaemia-reperfusion injury in the presence of hyperoxia. A total of 43 Wistar rats (WR), 30 spontaneously hypertensive rats (SHR) and 33 obese Zucker rats (ZR) were randomized in a sham procedure (one-third) or underwent a left anterior descending ligation of the coronary artery for 60 min (two-thirds). This was followed by 3 h of reperfusion while animals were randomized either in a hyperoxic (HR) or a normoxic reperfusion (NR) group. Myocardial infarction size and oxidative stress biomarkers (myeloperoxidase (MPO), malondialdehyde and total free thiols) were assessed in blood samples. Baseline troponin T was higher in SHR and ZR than in WR (both P < 0.001). Baseline total MPO was elevated in ZR in comparison to SHR and WR (both P < 0.001). SHR had lower thiol concentration compared to WR and ZR (P < 0.000001). HR was associated with a lower troponin T rise in SHR and ZR than in NR (both P < 0.001), while the reverse occurred in WR (P < 0.001). In SHR, HR limited total MPO increase as compared to NR (P = 0.0056) and the opposite effect was observed with total MPO in WR (P = 0.013). NR was associated with a drastic reduction of total thiols as compared to HR both in SHR and in ZR (both P < 0.001). Despite a heightened baseline oxidative stress level, HR limited myocardial necrosis and anti/pro-oxidant imbalance in SHR and ZR whereas this effect was exacerbated in healthy WR.


Subject(s)
Cardiovascular Diseases , Hyperoxia , Myocardial Reperfusion Injury , Animals , Rats , Heart Disease Risk Factors , Rats, Wistar , Rats, Zucker , Risk Factors
8.
Front Physiol ; 11: 926, 2020.
Article in English | MEDLINE | ID: mdl-32848866

ABSTRACT

BACKGROUND: While chemerin has been shown to increase proliferation and migration of systemic vascular smooth muscle cells (SMCs) contributing therefore to the development of hypertension, this remains to be clarified for the pulmonary circulation. METHODS: Expression of chemerin and its three receptors (CMKRL1, CCRL2, GPR1) was examined by immunohistochemistry and RTq-PCR in lungs, pulmonary artery, and thoracic aorta from Wistar rats. Primary cultured rat pulmonary artery and thoracic aorta SMCs treated with recombinant chemerin (tested from 5.10-9 to 10-7 mol/L) were assessed for proliferation and migration (both with 10-7 mol/L endothelin-1), as well as for staurosporine-induced apoptosis. RESULTS: In pulmonary artery and thoracic aorta, CMKLR1 expression was detected in both endothelial cells and SMCs. In primary cultured pulmonary artery SMCs, chemerin and its three receptors were expressed, and CMKLR1 expression was higher than those of CCRL2 and GPR1. Chemerin added to endothelin-1 increased pulmonary artery SMC proliferation, while chemerin or endothelin-1 alone did not. This effect was less pronounced in thoracic aorta SMCs. Chemerin induced pulmonary artery and thoracic aorta SMC migration, which was exacerbated by endothelin-1 and more pronounced in thoracic aorta SMCs. Chemerin concentration-dependently reduced staurosporine-induced apoptosis in both pulmonary artery and thoracic aorta SMCs. In pulmonary artery SMCs, endothelin-1 treatment increased the expression of CMKLR1, CCRL2, and GPR1, while these expressions were not altered in thoracic aorta SMCs. CONCLUSION: Chemerin/CMKRL1 signaling, in conjunction with a key mediator in the pathogenesis of pulmonary hypertensive diseases, endothelin-1, stimulated proliferation and migration, and increased resistance to apoptosis in rat primary cultured pulmonary artery SMCs. Our results suggest that this signaling could play a role in pulmonary artery remodeling observed in pulmonary hypertension.

9.
Lipids Health Dis ; 19(1): 123, 2020 Jun 03.
Article in English | MEDLINE | ID: mdl-32493392

ABSTRACT

BACKGROUND: In metabolic disorders, myocardial fatty infiltration is critically associated with lipotoxic cardiomyopathy. METHODS: Twenty Psammomys obesus gerbils were randomly assigned to normal plant or high fat diet. Sixteen weeks later, myocardium was sampled for pathobiological evaluation. RESULTS: A sixteen-week high fat diet resulted in myocardial structure disorganization, with collagen deposits, lipid accumulation, cardiomyocyte apoptosis and inflammatory cell infiltration. Myocardial expressions of glucose transporter GLUT1 and pyruvate dehydrogenase (PDH) inhibitor, PDH kinase (PDK)4 increased, while insulin-regulated GLUT4 expression remained unchanged. Myocardial expressions of molecules regulating fatty acid transport, CD36 and fatty acid binding protein (FABP)3, were increased, while expression of rate-controlling fatty acid ß-oxidation, carnitine palmitoyl transferase (CPT)1B decreased. Myocardial expression of AMP-activated protein kinase (AMPK), decreased, while expression of peroxisome proliferator activated receptors (PPAR)-α and -γ did not change. CONCLUSION: In high fat diet fed Psammomys obesus, an original experimental model of nutritionally induced metabolic syndrome mixing genetic predisposition and environment interactions, a short period of high fat feeding was sufficient to induce myocardial structural alterations, associated with altered myocardial metabolic gene expression in favor of lipid accumulation.


Subject(s)
Diet, High-Fat/adverse effects , Energy Metabolism/genetics , Gerbillinae/genetics , Myocardium/metabolism , Animals , Carnitine O-Palmitoyltransferase/genetics , Disease Models, Animal , Energy Metabolism/drug effects , Fatty Acid Binding Protein 3/genetics , Gene Expression Regulation/drug effects , Gerbillinae/metabolism , Glucose Transporter Type 1/genetics , Humans , Insulin/genetics , Insulin/metabolism , Metabolome/genetics , Myocardium/pathology , Oxidation-Reduction/drug effects , PPAR alpha/genetics , Protein Kinases/genetics
10.
Life Sci ; 231: 116580, 2019 Aug 15.
Article in English | MEDLINE | ID: mdl-31216440

ABSTRACT

AIMS: Chemerin has been recently identified as a vasoactive adipokine implicated in blood pressure regulation. In this context, we evaluated whether chemerin could influence pulmonary vasoreactive response. MATERIALS AND METHODS: Vascular reactivity to chemerin and to phenylephrine, serotonin and endothelin-1 after chemerin pretreatment was evaluated in rat isolated pulmonary artery versus thoracic aorta with and without endothelium. Vasoreactivity to acetylcholine in presence of nitric oxide (NO)-synthase inhibitor (L-NAME) and to NO donor sodium nitroprusside (SNP) was evaluated in chemerin-pretreated pulmonary artery versus thoracic aorta with endothelium. Pretreatment with ODQ, a soluble guanylate cyclase inhibitor and apocynin, a ROS production inhibitor, were also tested. Arteries and lung tissue were harvested for pathobiological evaluation. KEY FINDINGS: Chemerin contracted endothelium-denuded pulmonary artery, while no response was observed in arteries with endothelium. Chemerin potentiated phenylephrine-, endothelin-1- and serotonin-induced vasoconstriction, which was further enhanced by endothelium removal. Chemerin decreased acetylcholine-induced vasorelaxation in arteries with endothelium, while it did not affect SNP-induced relaxation. In presence of L-NAME, there remained a vasorelaxation in chemerin-pretreated arteries. Chemerin or ODQ alone partly decreased acetylcholine-induced vasorelaxation in pulmonary artery and thoracic aorta, while combined chemerin and ODQ incubation abolished it. Treatment with apocynin partly or totally reversed chemerin effects. In both types of arteries, chemerin reduced acetylcholine-induced NO production, as well as endothelial and inducible NO-synthase expression. SIGNIFICANCE: Chemerin potentiates vascular responses to vasoconstrictors in pulmonary artery and thoracic aorta and, impairs acetylcholine-induced pulmonary artery vasodilatation, by mechanisms involving at least partly NO signaling and oxidative stress.


Subject(s)
Chemokines/physiology , Intercellular Signaling Peptides and Proteins/physiology , Pulmonary Artery/drug effects , Vasoconstriction/drug effects , Acetylcholine/pharmacology , Adipokines/metabolism , Animals , Chemokines/metabolism , Endothelin-1/metabolism , Endothelins/drug effects , Endothelium, Vascular/drug effects , Intercellular Signaling Peptides and Proteins/metabolism , Male , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide/metabolism , Nitroprusside/pharmacology , Oxidative Stress/drug effects , Phenylephrine/pharmacology , Pulmonary Artery/metabolism , Rats , Rats, Wistar , Serotonin/metabolism , Thoracic Arteries/drug effects , Thoracic Arteries/metabolism , Vasoconstrictor Agents/pharmacology , Vasodilation/drug effects
11.
J Vet Emerg Crit Care (San Antonio) ; 29(3): 256-263, 2019 May.
Article in English | MEDLINE | ID: mdl-31034737

ABSTRACT

OBJECTIVE: To measure plasma N-terminal fragments of pro-B-type natriuretic peptides (NT-proBNP) and cardiac troponin T (cTnT) concentration in hospitalized dogs and relate these markers to underlying conditions and evaluate their potential as prognostic markers in dogs with systemic inflammatory response syndrome (SIRS). DESIGN: Prospective, observational, clinical study. SETTING: Emergency department of a university teaching hospital. ANIMALS: Sixty-nine dogs with SIRS examined in the emergency department were prospectively studied. Patient age ranged from 5 months to 15 years, and weight ranged from 5.5 to 75 kg. MEASUREMENTS AND MAIN RESULTS: Blood samples were obtained at presentation, during hospitalization until discharge or death, and at a "control" visit (T1m) at least 1 month after hospital discharge. NT-proBNP was assayed with a commercially available canine ELISA, while cTnT was measured with an automated immunoassay previously used in dogs. A correlation procedure, mixed procedure on a linear model, and a logistic procedure were performed. Forty-four patients survived, 19 of which had control visits. cTnT concentrations were significantly higher than T0 and T1m at T12, T24, and T72. In 28 dogs, cTnT was detected during hospitalization, but cTnT was not detected in any dog at the control visits. Higher concentrations of cTnT were negatively associated with survival, irrespective of disease category. NT-proBNP concentrations were significantly higher than T0, T6, T12, and T1m at T24, T72, and T120, but were not associated with survival. CONCLUSIONS: NT-proBNP and cTnT increased significantly in dogs with SIRS, regardless of the underlying disease process. Nonsurvivors displayed significantly higher cTnT concentrations during hospitalization.


Subject(s)
Biomarkers/blood , Dog Diseases/blood , Natriuretic Peptide, Brain/blood , Peptide Fragments/blood , Systemic Inflammatory Response Syndrome/veterinary , Troponin T/blood , Animals , Critical Care , Dogs , Female , Male , Prognosis , Prospective Studies , Systemic Inflammatory Response Syndrome/blood
12.
BMC Cardiovasc Disord ; 18(1): 99, 2018 05 21.
Article in English | MEDLINE | ID: mdl-29783950

ABSTRACT

BACKGROUND: Aortic regurgitation (AR) is a valvular disease that can lead to systolic heart failure. Treatment options besides cardiac surgery are limited and consequently severe AR is associated with higher mortality and morbidity when not operated. In this investigation, we examined the effects of a novel cardiac myosin activator, Omecamtiv-mecarbil (OM), in rats with chronic severe AR. METHODS: AR was created by retrograde puncture of the aortic valve leaflets in 20 adults Wistar rats. 12 animals survived the acute AR phase and were randomized 2 months thereafter into OM (n = 7) or placebo groups (n = 5). Two rats underwent a sham operation and served as controls. Equal volumes of OM or placebo (NaCl 0.9%) were perfused in the femoral vein by continuous infusion (1.2 mg/kg/hour) during 30 min. Doppler-echocardiography was performed before and at the end of the infusion periods. RESULTS: OM increased indices of global cardiac function (cardiac output, stroke volume), and increased systolic performance (fractional shortening, ejection fraction, left ventricular end systolic diameter) (all p < 0.05). These effects concurred with decreases in indices of LV preload (left atrial size, left ventricular end diastolic diameter) as well in the aortic pre-ejection period / left ventricular ejection time ratio (all p < 0.05). The severity score of the regurgitant AR jet did not change. Placebo infusion did not affect these parameters. CONCLUSION: The cardiac myosin activator OM exerts favorable hemodynamic effects in rats with experimental chronic AR.


Subject(s)
Aortic Valve Insufficiency/drug therapy , Aortic Valve/drug effects , Cardiac Myosins/metabolism , Cardiovascular Agents/administration & dosage , Hemodynamics/drug effects , Urea/analogs & derivatives , Ventricular Function, Left/drug effects , Animals , Aortic Valve/diagnostic imaging , Aortic Valve/metabolism , Aortic Valve/physiopathology , Aortic Valve Insufficiency/diagnostic imaging , Aortic Valve Insufficiency/metabolism , Aortic Valve Insufficiency/physiopathology , Chronic Disease , Disease Models, Animal , Echocardiography, Doppler , Infusions, Intravenous , Male , Rats, Wistar , Recovery of Function , Severity of Illness Index , Stroke Volume/drug effects , Urea/administration & dosage
13.
PLoS One ; 12(9): e0184368, 2017.
Article in English | MEDLINE | ID: mdl-28877257

ABSTRACT

Pulmonary fibrosis is characterized by over-population and excessive activation of fibroblasts and myofibroblasts disrupting normal lung structure and functioning. Rosemary extract rich in carnosic acid (CA) and rosmarinic acid (RA) was reported to cure bleomycin-(BLM)-induced pulmonary fibrosis. We demonstrate that CA decreased human lung fibroblast (HLF) viability with IC50 value of 17.13±1.06 µM, while RA had no cytotoxic effect. In the presence of 50 µM of RA, dose-response for CA shifted to IC50 value of 11.70±1.46 µM, indicating synergic action. TGFß-transformed HLF, rat lung fibroblasts and L929 cells presented similar sensitivity to CA and CA+RA (20µM+100µM, respectively) treatment. Rat alveolar epithelial cells died only under CA+RA treatment, while A549 cells were not affected. Annexin V staining and DNA quantification suggested that HLF are arrested in G0/G1 cell cycle phase and undergo apoptosis. CA caused sustained activation of phospho-Akt and phospho-p38 expression and inhibition of p21 protein.Addition of RA potentiated these effects, while RA added alone had no action.Only triple combination of inhibitors (MAPK-p38, pan-caspase, PI3K/Akt/autophagy) partially attenuated apoptosis; this suggests that cytotoxicity of CA+RA treatment has a complex mechanism involving several parallel signaling pathways. The in vivo antifibrotic effect of CA and RA was compared with that of Vitamine-E in BLM-induced fibrosis model in rats. We found comparable reduction in fibrosis score by CA, RA and CA+RA, attenuation of collagen deposition and normalization of oxidative stress markers. In conclusion, antifibrotic effect of CA+RA is due to synergistic pro-apoptotic action on lung fibroblasts and myofibroblasts.


Subject(s)
Abietanes/pharmacology , Apoptosis , Cinnamates/pharmacology , Depsides/pharmacology , Fibroblasts/drug effects , Animals , Bleomycin , Catalase/metabolism , Cell Cycle , Cell Line , Cell Movement , Cell Proliferation/drug effects , Collagen/metabolism , Humans , Hydroxyproline/metabolism , Inhibitory Concentration 50 , Lipid Peroxidation , Lung/cytology , Male , Mice , Oxidative Stress , Plant Extracts/pharmacology , Pulmonary Alveoli/metabolism , Pulmonary Fibrosis/drug therapy , Rats , Rats, Wistar , Signal Transduction , Superoxide Dismutase/metabolism , Vitamin E/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , Rosmarinic Acid
14.
PLoS One ; 12(7): e0181899, 2017.
Article in English | MEDLINE | ID: mdl-28753621

ABSTRACT

BACKGROUND: The mechanisms of brain death (BD)-induced lung injury remain incompletely understood, as uncertainties persist about time-course and relative importance of mechanical and humoral perturbations. METHODS: Brain death was induced by slow intracranial blood infusion in anesthetized pigs after randomization to placebo (n = 11) or to methylprednisolone (n = 8) to inhibit the expression of pro-inflammatory mediators. Pulmonary artery pressure (PAP), wedged PAP (PAWP), pulmonary vascular resistance (PVR) and effective pulmonary capillary pressure (PCP) were measured 1 and 5 hours after Cushing reflex. Lung tissue was sampled to determine gene expressions of cytokines and oxidative stress molecules, and pathologically score lung injury. RESULTS: Intracranial hypertension caused a transient increase in blood pressure followed, after brain death was diagnosed, by persistent increases in PAP, PCP and the venous component of PVR, while PAWP did not change. Arterial PO2/fraction of inspired O2 (PaO2/FiO2) decreased. Brain death was associated with an accumulation of neutrophils and an increased apoptotic rate in lung tissue together with increased pro-inflammatory interleukin (IL)-6/IL-10 ratio and increased heme oxygenase(HO)-1 and hypoxia inducible factor(HIF)-1 alpha expression. Blood expressions of IL-6 and IL-1ß were also increased. Methylprednisolone pre-treatment was associated with a blunting of increased PCP and PVR venous component, which returned to baseline 5 hours after BD, and partially corrected lung tissue biological perturbations. PaO2/FiO2 was inversely correlated to PCP and lung injury score. CONCLUSIONS: Brain death-induced lung injury may be best explained by an initial excessive increase in pulmonary capillary pressure with increased pulmonary venous resistance, and was associated with lung activation of inflammatory apoptotic processes which were partially prevented by methylprednisolone.


Subject(s)
Acute Lung Injury/etiology , Acute Lung Injury/physiopathology , Brain Death/pathology , Brain Death/physiopathology , Immunity, Humoral , Respiratory Mechanics , Acute Lung Injury/blood , Animals , Apoptosis , Brain Death/blood , Cell Adhesion Molecules/genetics , Cell Adhesion Molecules/metabolism , Female , Gene Expression Regulation , Hemodynamics , Interleukins/metabolism , Lung/pathology , Lung/physiopathology , Multivariate Analysis , Neutrophils/pathology , Oxidative Stress , Oxygen/metabolism , Partial Pressure , Peroxidase/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Sus scrofa , Tumor Necrosis Factor-alpha/metabolism
15.
PLoS One ; 12(1): e0169205, 2017.
Article in English | MEDLINE | ID: mdl-28085954

ABSTRACT

Decreased leptin-induced endothelium-dependent vasodilation has been reported in spontaneously hypertensive rats (SHR). Here, we report leptin-induced vasoconstriction in endothelium-denuded pulmonary artery and thoracic aorta from SHR and sought to characterize calcium handling underlying these mechanisms. Vasoreactivity to leptin was evaluated on pulmonary artery and thoracic aorta rings from 18 weeks old male SHR with or without calcium free medium, caffeine + thapsigargin + carbonyl cyanide-4-trifluoromethoxyphenylhydrazone emptying intracellular calcium stores, nifedipine a voltage-gated calcium channel inhibitor, SKF-96365 a transient receptor potential cation channels (TRPC) inhibitor, wortmaninn, a phosphatidylinositide 3-kinases (PI3K) inhibitor, or PD98059 a mitogen-activated protein kinase kinase (MAPKK) inhibitor. Calcium imaging was performed on cultured vascular smooth muscle cells incubated with leptin in presence or not of wortmaninn or PD98059. Leptin induced vasoconstriction in denuded pulmonary artery and thoracic aorta from SHR. Response was abolished when intra- or extracellular calcium stores were emptied, after blocking TRPC or voltage-dependent calcium channels or when using MAPKK or PI3K inhibitors. In vascular smooth muscle cells, leptin increased intracellular calcium. This rise was higher in SHR and abolished by MAPKK or PI3K inhibitors. TRPC6 gene expression was upregulated in arteries from SHR. Leptin-induced vasoconstriction in denuded arteries of SHR requires intracellular stores and is TRPC- and voltage-gated calcium channels dependent. Intracellular calcium increase is more pronounced in spontaneously hypertensive rats.


Subject(s)
Aorta, Thoracic/drug effects , Calcium/metabolism , Endothelium, Vascular/drug effects , Hypertension/physiopathology , Leptin/metabolism , Pulmonary Artery/drug effects , Vasoconstriction/drug effects , Animals , Aorta, Thoracic/metabolism , Cells, Cultured , Endothelium, Vascular/metabolism , Leptin/administration & dosage , Male , Mitogen-Activated Protein Kinase Kinases/metabolism , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Pulmonary Artery/metabolism , Rats , Rats, Inbred SHR , Rats, Wistar
16.
Vet J ; 194(1): 34-9, 2012 Oct.
Article in English | MEDLINE | ID: mdl-23022110

ABSTRACT

B-type natriuretic peptide or brain natriuretic peptide (BNP) is a cardiac peptide hormone. The principal stimulus for BNP synthesis is myocyte stretch. BNP binds to the natriuretic peptide receptor-A causing increased intracellular cyclic guanosine monophosphate (cGMP) production and shows cardio- and renoprotective effects. However, high endogenous BNP levels are associated with a lack of effect in severe heart failure. Moreover, in experimental heart failure, the response to treatments targeting the natriuretic peptide system is attenuated. This article reviews potential mechanisms that may explain the 'BNP paradox' in heart failure with a focus on interspecies differences, on known and presumed specificities of canine BNP biology, and on experimental studies in dogs. Resistance to BNP is far from fully understood but may be due to post-translational modifications and alteration in proBNP processing, receptor downregulation and desensitization, blunted intracellular signalling and increased clearance of BNP(1-32.) Alternatively, resistance to BNP may be due to BNP(1-32) shortening into additional truncated forms that are less biologically effective. Future improvement in understanding of BNP biology may provide the rationale for innovative therapeutic strategies to maximize cardiovascular and renal cGMP bioavailability.


Subject(s)
Dog Diseases/metabolism , Heart Failure/veterinary , Natriuretic Peptide, Brain/metabolism , Animals , Dogs , Heart Failure/metabolism , Species Specificity
17.
Eur J Heart Fail ; 14(1): 14-21, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22045924

ABSTRACT

AIMS: Recent studies indicate that brain natriuretic peptide (BNP(1-32)) may be truncated into BNP(3-32) by dipeptidyl peptidase IV (DPP4) and that BNP(3-32) has reduced biological activities compared with BNP(1-32). We investigated if DPP4 contributes to the cardiorenal alterations and to the attenuated response to BNP seen in heart failure. METHODS AND RESULTS: Haemodynamic and renal assessment was performed in 12 pigs at baseline, 4 weeks after pacing-induced heart failure, and during BNP infusion. They were randomized to either placebo or treatment with a DPP4 inhibitor, sitagliptin. After 4 weeks of pacing, heart rate was reduced compared with baseline in the sitagliptin group (60 ± 2 vs. 95 ± 16 b.p.m., P < 0.01), and an increase in stroke volume was observed in the sitagliptin group compared with placebo (+24 ± 6% vs. -17 ± 7%, P < 0.01). Glomerular filtration rate declined at week 4 compared with baseline in the placebo group (1.3 ± 0.4 vs. 2.3 ± 0.3 mL/kg/min, P < 0.01) but remained preserved in the sitagliptin group [1.8 ± 0.2 vs. 2.0 ± 0.3 mL/kg/min, P = NS (non-significant)]. In the sitagliptin group, BNP infusion improved end-systolic elastance (68 ± 5 vs. 31 ± 4 mmHg/kg/mL, P < 0.05), ventricular-arterial coupling, and mechanical efficiency. Compared with controls (n = 6), myocardial gene expression of BNP, interleukin-6, Na(+)-Ca(2+) exchanger, and calmodulin was up-regulated in the placebo group, but not in the sitagliptin group. CONCLUSION: In pacing-induced heart failure, DPP4 inhibition preserves the glomerular filtration rate, modulates stroke volume and heart rate, and potentiates the positive inotropic effect of exogenous BNP at no energy expense.


Subject(s)
Cardiac Pacing, Artificial/methods , Dipeptidyl Peptidase 4/metabolism , Heart Failure , Natriuretic Peptide, Brain/metabolism , Pyrazines/administration & dosage , Triazoles/administration & dosage , Animals , Calmodulin/metabolism , Dipeptidyl-Peptidase IV Inhibitors/administration & dosage , Disease Models, Animal , Female , Glomerular Filtration Rate/drug effects , Heart Failure/etiology , Heart Failure/metabolism , Heart Rate/drug effects , Hemodynamics/drug effects , Interleukin-6/metabolism , Sitagliptin Phosphate , Sodium-Calcium Exchanger/metabolism , Swine
18.
Clin Chim Acta ; 413(3-4): 456-62, 2012 Feb 18.
Article in English | MEDLINE | ID: mdl-22093941

ABSTRACT

BACKGROUND: Dipeptidyl peptidase IV (DPPIV, DPP4) is a serine protease that releases N-terminal dipeptides. It is a validated drug target for type 2 diabetes and DPPIV inhibitors are currently evaluated for other therapeutic applications. Various assays are used for DPPIV activity measurements in biological samples. Highly sensitive methods are needed to measure also very low activities in inhibited samples. METHODS: Here, the three most extensively used substrates to quantify DPPIV activity are compared using in-house methods. A luminescent kit was also included. In addition, one of the in-house fluorometric assays was elaborated for use in biological samples containing reversible DPPIV inhibitors to estimate residual DPPIV activity which is usually underestimated due to sample dilution. RESULTS: The in-house methods showed a good precision, linearity and specificity. Both fluorometric substrates had a 10-fold higher sensitivity compared to the colorimetric assay. The luminescent kit was found to be the most sensitive. CONCLUSIONS: All three in-house methods can be used to measure DPPIV activity in non-inhibited biological samples. The more sensitive fluorometric assays are recommended when sample volumes are limited or when using inhibited samples. The elaborated fluorometric method can be used to estimate the residual in vivo DPPIV activity in inhibitor treated subjects.


Subject(s)
Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Enzyme Assays/methods , Analytic Sample Preparation Methods , Animals , Colorimetry , Dipeptidyl Peptidase 4/blood , Fluorometry , Humans , Kinetics , Linear Models , Mice
19.
BMC Cardiovasc Disord ; 10: 32, 2010 Jun 29.
Article in English | MEDLINE | ID: mdl-20587034

ABSTRACT

BACKGROUND: Heart failure with preserved left ventricular ejection fraction and abnormal diastolic function is commonly observed after recovery from an acute myocardial infarction. The aim of this study was to investigate the physiopathology of heart failure with preserved ejection fraction in a model of healed myocardial infarction in dogs. METHODS: Echocardiography, levels of neurohormones and conductance catheter measurements of left ventricular pressure-volume relationships were obtained in 17 beagle dogs 2 months after a coronary artery ligation, and in 6 controls. RESULTS: Healed myocardial infarction was associated with preserved echocardiographic left ventricular ejection fraction (0.57 +/- 0.01, mean +/- SEM) and altered Doppler mitral indices of diastolic function. NT-proBNP was increased, aldosterone was decreased, and norepinephrine was unchanged. Invasive measurements showed a markedly decreased end-systolic elastance (2.1 +/- 0.2 vs 6.1 +/- 0.8, mmHg/ml, p < 0.001) and end-systolic elastance to effective arterial elastance ratio (0.6 +/- 0.1 vs 1.4 +/- 0.2, p < 0.001), with altered active relaxation (dP/dtmin -1992 +/- 71 vs -2821 +/- 305, mmHg/s, p < 0.01) but preserved left ventricular capacitance (70 +/- 6 vs 61 +/- 3, ml at 20 mmHg, p = NS) and stiffness constant. Among echocardiographic variables, the wall motion score index was the most reliable indicator of cardiac contractility while E', E/A and E'/A' were correlated to dP/dtmin. CONCLUSIONS: In the canine model of healed myocardial infarction induced by coronary ligation, heart failure is essentially characterized by an altered contractility with left ventricular-arterial uncoupling despite vascular compensation rather than by abnormal diastolic function.


Subject(s)
Heart Failure/diagnostic imaging , Heart Failure/surgery , Myocardial Infarction/diagnostic imaging , Myocardial Infarction/surgery , Animals , Coronary Artery Bypass , Diastole , Dogs , Echocardiography , Excitation Contraction Coupling , Heart Failure/etiology , Heart Function Tests , Hemodynamics , Humans , Models, Animal , Myocardial Contraction , Myocardial Infarction/complications , Stroke Volume
20.
BMC Cardiovasc Disord ; 9: 49, 2009 Oct 09.
Article in English | MEDLINE | ID: mdl-19818143

ABSTRACT

BACKGROUND: Insulin-like growth factor-1 (IGF-1), transforming growth factor beta (TGFbeta) and cyclins are thought to play a role in myocardial hypertrophic response to insults. We investigated these signaling pathways in canine models of ischemic or overpacing-induced cardiomyopathy. METHODS: Echocardiographic recordings and myocardial sampling for measurements of gene expressions of IGF-1, its receptor (IGF-1R), TGFbeta and of cyclins A, B, D1, D2, D3 and E, were obtained in 8 dogs with a healed myocardial infarction, 8 dogs after 7 weeks of overpacing and in 7 healthy control dogs. RESULTS: Ischemic cardiomyopathy was characterized by moderate left ventricular systolic dysfunction and eccentric hypertrophy, with increased expressions of IGF-1, IGF-1R and cyclins B, D1, D3 and E. Tachycardiomyopathy was characterized by severe left ventricular systolic dysfunction and dilation with no identifiable hypertrophic response. In the latter model, only IGF-1 was overexpressed while IGF-1R, cyclins B, D1, D3 and E stayed unchanged as compared to controls. The expressions of TGFbeta, cyclins A and D2 were comparable in the 3 groups. The expression of IGF-1R was correlated with the thickness of the interventricular septum, in systole and diastole, and to cyclins B, D1, D3 and E expression. CONCLUSION: These results agree with the notion that IGF-1/IGF-1R and cyclins are involved in the hypertrophic response observed in cardiomyopathies.


Subject(s)
Arrhythmias, Cardiac/complications , Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Hypertrophic/genetics , Cyclins/genetics , Insulin-Like Growth Factor I/genetics , Myocardial Ischemia/complications , Myocardium/metabolism , Animals , Arrhythmias, Cardiac/diagnostic imaging , Arrhythmias, Cardiac/genetics , Arrhythmias, Cardiac/metabolism , Cardiac Pacing, Artificial , Cardiomyopathy, Dilated/diagnostic imaging , Cardiomyopathy, Dilated/metabolism , Cardiomyopathy, Hypertrophic/diagnostic imaging , Cardiomyopathy, Hypertrophic/metabolism , Cyclins/metabolism , Disease Models, Animal , Dogs , Echocardiography , Gene Expression Regulation , Insulin-Like Growth Factor I/metabolism , Myocardial Ischemia/diagnostic imaging , Myocardial Ischemia/genetics , Myocardial Ischemia/metabolism , Myocardium/pathology , Polymerase Chain Reaction , Receptor, IGF Type 1/genetics , Transforming Growth Factor beta/genetics , Ventricular Dysfunction, Left/genetics , Ventricular Dysfunction, Left/metabolism
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