Folic acid restores endothelial function in ACTH-induced hypertension

AbstractHypertension is associated with increased oxidative stress and vascular endothelium dysfunction. The aim was to study the effect of folic acid (FA) on hypertension, blood nitric oxide (NO), homocysteine (HCY), malondialdehyde (MDA) and reduced glutathione (GSH); aortic tissue glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD); and vascular endothelial function in adrenocorticotrophic hormone (ACTH)-induced hypertension rats. Rats were treated with saline or FA alone (0.04g/L/day orally, control), or subcutaneous ACTH-induced hypertension (0.2mg/kg/day, ACTH) groups. Treated FA groups were started before (Folic–ACTH, prevention) and during (ACTH–Folic, reversal) ACTH administrations. Systolic blood pressure (SBP), thymus/body weight ratio, blood urea, creatinine, NO, HCY, MDA and GSH; aortic endothelium-dependent vasodilator (EDD) in response to acetylcholine (ACh), aortic tissue extract for CAT, GPx, and SOD activity; and histopathological changes of aorta and kidney were assessed. Saline or FA alone did not change SBP (P>0.05). FA, in prevention study, significantly decreased SBP, increased serum NO and GSH, enhanced relaxation response (EDD%) to 1×10−4M ACh; increased aortic tissue GPx, CAT and SOD activity, also revealed nearly normal endothelial cell layer and moderately positive cytoplasmic staining for CD34+ expression versus ACTH-treated rats (P<0.05). In contrast, FA, in reversal study, did not show significant changes in most of the measured parameters as ACTH-treated group (P>0.05). FA can be used as an adjuvant therapy for prevention and treatment of ACTH-induced hypertension. The protective role of FA in ACTH-induced hypertension could be attributed via decreasing HCY, MDA (oxidative stress); increasing NO, GSH, GPx, CAT, SOD activity (antioxidants); and restoring endothelial dysfunction

BMP-7 Attenuates Inflammation-Induced Pyroptosis and Improves Cardiac Repair in Diabetic Cardiomyopathy

In the present study, we investigated a novel signaling target in diabetic cardiomyopathy where inflammation induces caspase-1-dependent cell death, pyroptosis, involving Nek7-GBP5 activators to activate the NLRP3 inflammasome, destabilizes cardiac structure and neovascularization. Furthermore, we explored the therapeutic ability of bone morphogenetic protein-7 (BMP-7) to attenuate these adverse effects. C57BL/6J mice (n = 16 mice/group) were divided into: control (200 mg/kg, 0.9% saline intraperitoneal injection, i.p.); Streptozotocin (STZ) and STZ-BMP-7 groups (STZ, 200 mg/kg, i.p. injection). After 6 weeks, heart function was examined with echocardiography, and mice were sacrificed. Immunostaining, Western blotting, H&amp;E, and Masson’s trichrome staining was performed on heart tissues. STZ-induced diabetic cardiomyopathy significantly increased inflammasome formation (TLR4, NLRP3, Nek7, and GBP5), pyroptosis markers (caspase-1, IL-1β, and IL-18), inflammatory cytokines (IL-6 and TNF-α), MMP9, and infiltration of monocytes (CD14), macrophage (iNOS), and dendritic cells (CD11b and CD11c) (p &lt; 0.05). Moreover, a significant endothelial progenitor cells (EPCs) dysfunction (c-Kit/FLk-1, CD31), adverse cardiac remodeling, and reduction in left ventricular (LV) heart function were observed in STZ versus control (p &lt; 0.05). Treatment with BMP-7 significantly reduced inflammasome formation, pyroptosis, and inflammatory cytokines and infiltrated inflammatory cells. In addition, BMP-7 treatment enhanced EPC markers and neovascularization and subsequently improved cardiac remodeling in a diabetic heart. Moreover, a significant improvement in LV heart function was achieved after BMP-7 administration relative to diabetic mice (p &lt; 0.05). In conclusion, BMP-7 attenuated inflammation-induced pyroptosis, adverse cardiac remodeling, and improved heart function via the TLR4-NLRP3 inflammasome complex activated by novel signaling Nek7/GBP5. Our BMP-7 pre-clinical studies of mice could have significant potential as a future therapy for diabetic patients

Dataset for: Tadalafil, a long acting phosphodiesterase inhibitor, promotes bone marrow stem cell survival and their homing into ischemic myocardium for cardiac repair

The aim was to evaluate the tadalafil-mediated effects at molecular level on bone marrow-derived mesenchymal stem cells (MSCs) survival and their homing into the infarcted hearts to promote cardiac repair and improve function. MSCs were pretreated in vitro with tadalafil (+/-H2O2, oxidative stress) and with PKG, MAPK, FasL, nitric oxide synthase (NOS) (L-NAME), CXCR4 (AMD3100), or miR-21 inhibitors (+/-luciferase construction +/-Fas) for 2h before tadalafil. Rats were subjected to acute myocardial infarction (AMI), and then followed by injection of saline or 1.5x106 MSCs-treated +/- tadalafil into infarcted area. In another group, AMI was performed in 1-month post-myelo-ablated rats, were injected intraperitoneally (IP) with tadalafil +/- AMD3100 or L-NAME for 5 days. Also, in another group, AMI mice were treated with IP +/- tadalafil before intravenous injection with 111In-oxine-MSCs followed by CT/SPECT imaging to locate mobilized MSCs. Cardiac function was assessed by echocardiography. MSCs and heart extracts were analyzed by molecular bioassays. Tadalafil-treated MSCs had higher expression of cGMP, NOS, SDF-1α, p-VASP, p-Erk1/2, p-STAT3, p-Akt, PKG1 and Bcl-xl; expression of these molecules was reduced with PKG1, MAPK, NOS or FasL inhibitors. Tadalafil inhibited apoptosis through increased miR-21 expression and improved cell survival by inhibiting Fas (restored by PKG1, MAPK or miR-21 inhibitors). In vivo, heart function, grafted cell survival, MSCs mobilization and homing were improved in tadalafil-treated AMI animals versus controls. Conclusions: Tadalafil prolonged MSCs survival via up-regulation of miR-21 dependent suppression of Fas, and increased MSCs mobilization and their homing into infarcted myocardium resulting in improved cardiac repair and function

Atorvastatin improves cardiac function and remodeling in chronic non-ischemic heart failure: A clinical and pre-clinical study

Aims: The aim was to evaluate the cardio-protective effect of atorvastatin in combination with standard chronic heart failure (CHF) therapy that might improve cardiac function, remodeling, and further delay the progression of CHF in patients and rats. Methods and results: CHF patients (n = 20 per group) with left ventricular ejection fraction (LV-EF) <45% were randomized into: standard anti-failure treatment alone (controls) and standard anti-failure treatment plus atorvastatin (40 mg/day) for 6 weeks. After 6 weeks, the patients were assessed using echocardiography. Laboratory evaluation for lipid profiles, high sensitive C-reactive protein (hs-CRP), cardiac troponin-T (cTnT) and malondialdehyde (MDA) were performed in all patients. In parallel, rats (n = 10 per group) received treatment for 4 weeks and were divided as follows: saline treated (control, 1 ml intraperitoneal, IP), doxorubicin treated (2.5 mg/kg, IP), atorvastatin–doxorubicin treated (10 mg/kg, orally), and digoxin–doxorubicin treated (0.02 mg/kg, orally). The same laboratory analysis including histopathology of heart tissues was performed on the rats. In patients, atorvastatin improved heart function (increased LV-EF%, LV-fraction shorting (LV-FS%), and E/A velocity ratio; decreased LV-end diastolic diameter (LV-EDD) and LV-end systolic diameter (LV-ESD)) and significantly reduced serum lipid profiles, cTnT, hs-CRP and MDA versus patient controls. In rats, atorvastatin improved signs of CHF, systolic blood pressure, reduced serum lipid profiles, cTnT, hs-CRP and tissue MDA; less cardiac necrosis and fibrosis with enhancement of neo-vascularization versus other doxorubicin-treated rats. Conclusions: Atorvastatin with standard CHF therapy improved cardiac function and remodeling. Cardio-protective “pleiotropic” actions of atorvastatin are anti-inflammatory, anti-fibrotic and anti-oxidative. Thus, atorvastatin has a potential therapeutic value in the management of CHF patients

The value of urotensin II in patients with left-sided rheumatic valvular regurgitation

Aims: Rheumatic valve diseases are most common etiological valve diseases in developing countries. Urotensin II is cardiovascular autacoid/hormone and may be associated with patients of heart valve diseases. The present study was to measure plasma urotensin II concentrations in patients with left-sided rheumatic valve diseases such as mitral regurgitation (MR) and aortic regurgitation (AR), and to examine its correlation with severity of valve impairment, function (New York Heart association, NYHA) class and pulmonary artery pressure (PAP). Methods and results: Sixty patients with moderate to severe rheumatic left-sided valve regurgitation and 20 healthy controls were selected after performing the echocardiography. Plasma urotensin II level was measured in all subjects. The patients with MR and AR were significantly increased of left ventricular end diastolic dimension (LVEDD), left ventricular end systolic dimension (LVESD), left atrial diameter, PAP, but decreased of EF% versus the controls. Urotensin II level was highly significant in patients with MR (1.83 ± 0.92 ng/ml, P < 0.001) and AR (0.79 ± 0.3 ng/ml, P < 0.05) versus the controls (0.48 ± 0.13 ng/ml). Also, there was significant correlation between Urotensin II level and LVEDD (MR, r = 0.318, P = 0.03; AR, r = 0.805, P < 0.001), LVESD (MR, r = −0.271, P = 0.115; AR, r = 0.614, P = 0.001), and PAP (MR, r = 0.706, P < 0.001; AR, r = 0.129, P = 0.538). Conclusion: Urotensin II was elevated in patients with rheumatic left-sided valvular regurgitation, and positively correlated with increased LVEDD (in both MR and AR), LVESD (only AR) and pulmonary artery pressure (only MR). Therefore, urotensin II level may be used as diagnostic biomarker in patients with rheumatic valvular diseases for assessment of the severity in parallel with echocardiography

Optimization of in vitro vascular cell transfection with non-viral vectors for in vivo applications

Syngeneic vascular cells are interesting tools for indirect gene therapy in the cardiovascular system. This study aims to optimize transfection conditions of primary cultures of vascular smooth muscle cells (VSMCs) using different non-viral vectors and zinc as an adjuvant and to implant these transfected cells in vivo

Relationship of apolipoprotein E polymorphism with lipid profiles in atherosclerotic coronary artery disease

Aims: The aim was to determine the relationship between apolipoprotein E (ApoE) gene polymorphisms and lipid profile in patients with coronary artery diseases (CAD), and its role in the prediction of the severity of carotid and coronary atherosclerosis. Methods and results: One hundred patients were classified by coronary angiography: 80 patients with CAD and 20 controls (normal coronary angiography). Clinical data, carotid sonography, blood lipid profiles and ApoE genotyping (PCR-RFLP) were assessed. CAD patients had significantly increased plasma lipid profiles and carotid intimal-wall thickness (IMT) versus controls. In CAD patients; ApoE genotype frequencies were E3/E3 = 62.50%, E2/E3 = 18.75%, E3/E4 = 17.50%, E2/E4 = 1.25%, E4/E4 = 0 and E2/E2 = 0. But, E3/E4 genotype was significantly higher than controls (P < 0.05). Also, in CAD patients; ApoE allele frequencies were E3 = 80.6%, E2 = 10.0% and E4 = 9.4% but, ApoE4 alleles were associated with higher cholesterol (P = 0.034) and LDL-c (P = 0.003), while ApoE2 alleles were associated with higher triglycerides (P = 0.037) versus ApoE3 alleles. However, odds ratio of CAD patients had higher risk with E2/E3 genotypes (2.5-fold), E2 alleles (2.2-fold) and E4 alleles (2.1-fold). Moreover, CAD patients with ApoE4 alleles had significantly higher carotid IMT (1.23 ± 0.26 mm vs 0.97 ± 0.2 mm ApoE3, P = 0.006; however, non-significant vs 1.10 ± 0.40 mm ApoE2 and also, ApoE2 vs ApoE3 alleles, P = 0.633) and left anterior descending (LAD) coronary artery stenosis (vs ApoE3 alleles, P = 0.016). Conclusion: Ischemic patients with carotid and coronary atherosclerosis had significantly higher integration of dyslipidemia and ApoE alleles (ApoE2 with hypertriglyceridemia and ApoE4 with hypercholesterolemia and higher LDL-c). ApoE polymorphism may be an important diagnostic risk biomarker and may implicate therapeutic intervention in atherosclerotic ischemic patients