Role of TNF-α in vascular dysfunction

Healthy vascular function is primarily regulated by several factors including EDRF (endothelium-dependent relaxing factor), EDCF (endothelium-dependent contracting factor) and EDHF (endothelium-dependent hyperpolarizing factor). Vascular dysfunction or injury induced by aging, smoking, inflammation, trauma, hyperlipidaemia and hyperglycaemia are among a myriad of risk factors that may contribute to the pathogenesis of many cardiovascular diseases, such as hypertension, diabetes and atherosclerosis. However, the exact mechanisms underlying the impaired vascular activity remain unresolved and there is no current scientific consensus. Accumulating evidence suggests that the inflammatory cytokine TNF (tumour necrosis factor)-α plays a pivotal role in the disruption of macrovascular and microvascular circulation both in vivo and in vitro. AGEs (advanced glycation end-products)/RAGE (receptor for AGEs), LOX-1 [lectin-like oxidized low-density lipoprotein receptor-1) and NF-κB (nuclear factor κB) signalling play key roles in TNF-α expression through an increase in circulating and/or local vascular TNF-α production. The increase in TNF-α expression induces the production of ROS (reactive oxygen species), resulting in endothelial dysfunction in many pathophysiological conditions. Lipid metabolism, dietary supplements and physical activity affect TNF-α expression. The interaction between TNF-α and stem cells is also important in terms of vascular repair or regeneration. Careful scrutiny of these factors may help elucidate the mechanisms that induce vascular dysfunction. The focus of the present review is to summarize recent evidence showing the role of TNF-α in vascular dysfunction in cardiovascular disease. We believe these findings may prompt new directions for targeting inflammation in future therapies

Combination Therapy of Brain Natriuretic Peptide and Sildenafil Attenuates Pulmonary Hypertension in Rats [abstract]

Abstract only availableFaculty Mentor: Dr. Vincent DeMarco, Child HealthBackground: Pulmonary arterial hypertension (PAH) is a lethal disease characterized by changes in pulmonary vascular structure and function. We tested the hypothesis that Sildenafil, a phosphodiesterase 5 inhibitor, and brain natriuretic peptide (BNP), a guanosine cyclase stimulator, in combination synergistically attenuates PAH when compared to individual therapy in rats through different mechanisms to increase cGMP while minimizing systemic side effects. Methods: Adult male Sprague-Dawley rats were subcutaneously injected with monocrotaline (n=30, 50 mg/kg). After approximately 5 weeks, rats were anesthetized and instrumented to measure systemic pressure (MAP) and right ventricular systolic pressure (RVSP) during infusions of vehicle solution (n=5), intravenous Sildenafil (84 mg/kg/min; n=8), and intravenous BNP (100 ng/kg/min; n=7) alone and a combination of Sildenafil and BNP (n=10). Results: Sildenafil alone decreased RVSP (-17 ±13.2 mmHg) and had a relatively minimal effect on MAP (-4±9.9 mmHg). BNP decreased RVSP (-19±14 mmHg) but also significantly effected MAP (-11±15.3mmHg). Combination therapy with Sildenafil and BNP lowered RVSP (-20±18.7 mmHg), however it also induced the greatest systemic hypotensive effect (MAP = -19±9.9 mmHg). Conclusion: The combination of Sildenafil and BNP, at these doses, significantly attenuates monocrotaline-induced pulmonary hypertension. However, compared with individual treatment, there is no significant difference in effect on RVSP. Furthermore, additive systemic side effects are too significant to consider combination therapy safe. With a different dosing regime, this combination is a potentially viable option in the treatment of patients with PAH

Cardiorenal Syndrome: The Clinical Cardiologists’ Perspective

The term cardiorenal syndrome has evolved over the years. The understanding of the interactions between these two organ systems has led to better recognition and treatment strategies. As cardiovascular mortality is high in individuals with renal dysfunction, it is imperative to understand the pathophysiology behind the disease process. This knowledge may better serve these patients with this syndrome and improve their outcomes. In this review, we examine the key issues of the cardiorenal syndrome from a cardiologist's perspective

Dynamic left ventricular outflow tract obstruction : clinical and echocardiographic risk factor association in critically ill patients

Journal Article published 6 Aug 2016 in Research in Cardiovascular Medicine, volume Inpress, issue Inpress..Originally published: Mittal, M. K., Pak, Y., Dellsperger, K. C., & Chockalingam, A. (2016). Dynamic Left Ventricular Outflow Tract Obstruction: Clinical and Echocardiographic Risk Factor Association in Critically Ill Patients. Research in Cardiovascular Medicine, Inpress(Inpress). doi:10.5812/cardiovascmed.35012Background: Dynamic left ventricular outflow tract obstruction (LVOTO) is increasingly recognized in critically ill patients and is a cause of significant morbidity and mortality. OBJECTIVES: To identify clinical risk predictors that may identify patient at high-risk of developing LVOTO based on their echocardiographic features. METHODS: Clinical and demographic data of all patients diagnosed with acute LVOTO were matched with a randomly derived control group to develop a clinical scoring model (development cohort). Subsequently, a cross sectional study was conducted to validate the scoring model using 143 consecutive patients admitted to intensive care units who underwent echocardiography (validation cohort). A blinded observer classified all patients as either high or low echocardiographic risk for developing LVOTO. Results: The retrospective cross sectional study (of validation cohort) could not validate the clinical score (developed from the development cohort) because it did not differentiate between different LVOTO risk groups (P = 0.54). Univariate analysis suggested female gender (high vs low risk, 64% vs 32%; P = 0.009), age > 60 years (74.8 14.1 vs 57.8 18.4; P = 0.0004) and lack of inotrope use (35% vs 61%; P = 0.03) to be significantly associated with high-risk LVOTO group. All other variables were statistically non-significant. Based on the multiple logistic regression analysis, age > 60 (P = 0.003) was found to be the only independent predictor of high risk for developing LVOTO, with the estimated area under the ROC curve being 0.81. CONCLUSIONS: Elderly patients are at high risk of developing dynamic LVOTO. Other clinical and demographic parameters did not reliably predict risk in our study. Further studies are warranted to improve risk prediction and identification of this, rare but potentially life threatening, cardiac condition before its clinical manifestation.Mayank K Mittal (1), Youngju Pak (2), Kevin C Dellsperger (3) and Anand Chockalingam (1). -- 1) Division of Cardiovascular Medicine, Department of Medicine, University of Missouri--Columbia, Missouri, United States ; 2) Department of Biostatistics, UCLA Clinical and Translational Science Institute, Torrance, CA, United States ; 3) Georgia Regents Health System, Augusta, GA, United States ; Corresponding author: Anand Chockalingam, Associate Professor of Clinical Medicine, Division of Cardiology, University of Missouri--Columbia

Pulmonary Vascular Remodeling in Transgenic Ren 2 Rats [abstract]

Abstract only availableFaculty Mentor: Dr. Vincent DeMarco, Child HealthAngiotensin II is a vasoconstrictor that causes endothelial dysfunction, vascular remodeling, and hypertension. Statins improve vascular endothelial cell function and inhibit vascular endothelial and smooth muscle cell proliferation. In this study, we examined the pulmonary vasculature of Ren-2 transgenic rats (TGR(mREN-2)27) that exhibit tissue level overexpression of the mouse renin gene, a precursor to Angiotensin II. We hypothesized that Ren-2 rats exhibit pulmonary hypertension (PH) similar to humans, i.e. increases in pulmonary vascular resistance, vascular remodeling, and right ventricular hypertrophy. We also hypothesized that the severity of PH in Ren-2 rats may be reduced by the 3-hydroxy-3-methylglultaryl coenzyme A reductase inhibitor, rosuvastatin. Male Sprague-Dawley rats and Ren-2 rats were randomly assigned to one of four treatment groups: Sprague-Dawley untreated (n=13), Ren-2 untreated (n=10), Sprague-Dawley Statin treated (n=6), Ren-2 Statin treated (n=9). Rosuvastatin was administered daily by IP injection in 10mg/kg and 20mg/kg doses (no difference was found between dose groups). Three weeks after treatment began lung tissues were harvested for analysis. Morphometric analysis showed significant vascular remodeling of the pulmonary arterioles in the Ren-2 untreated groups; a decrease in area of the lumen and an increase in area of the media. Right ventricular hypertrophy, a symptom of PH, was not found. eNOS (endothelial nitric oxide synthase) levels were elevated in untreated Ren-2 rats compared to Sprague-Dawley untreated; NO levels in the lung were similar between the two groups indicating a possible compensatory mechanism. These data suggest that young Ren-2 rats are at risk for developing pulmonary hypertension. Further studies are needed in older Ren-2 rats in order to determine the stage and severity at which pulmonary hypertension develops. Finally, statin treatment prevents or reverses vascular remodeling in Ren-2 rats and could reduce risk of developing PH.Life Sciences Undergraduate Research Opportunity Progra

Lung tissue expression of angiotensinogen in ren-2 rats [abstract]

Abstract only availablePulmonary hypertension (PH) is a rapidly progressive disease that results in death. PH is characterized by increased vascular resistance, vascular remodeling, and right ventricular hypertrophy. Increased levels of ANG II lead to increased vasoconstriction, an increase in the number of vascular smooth muscle cells, hypertrophy, fibrosis, and vascular inflammation. A major contributor to PH could be lung tissue overexpression of the RAS because the RAS is a cascade of enzymes and peptides that ultimately for ANG II. Angiotensinogen is an inactive peptide produced by the liver and circulated systemically. ANG II is produced through the enzymatic reaction of renin cleaving angiotensinogen forming angiotensin I which is then converted into ANG II by angiotensin converting enzyme (ACE). In this study, we will look at lung tissue levels of angiotensinogen and where it is primarily found in the lung using indirect immunofluorescence microscopy. The lung sections will be from transgenic (TGR (mREN-2)27 (Ren-2) rats which overexpress ANG II and have been found to exhibit PH at 8-9 weeks of age. We hypothesize that angiotensinogen will be expressed throughout the lung particularly in the vascular wall, the endothelial cells and smooth muscle cells, in increased levels in Ren-2 rats compared to age matched Sprague-Dawley controls in which angiotensinogen is expressed at normal levels.Life Sciences Undergraduate Research Opportunity Progra

Contribution of oxidative stress to pulmonary arterial hypertension

Recent data implicate oxidative stress as a mediator of pulmonary hypertension (PH) and of the associated pathological changes to the pulmonary vasculature and right ventricle (RV). Increases in reactive oxygen species (ROS), altered redox state, and elevated oxidant stress have been demonstrated in the lungs and RV of several animal models of PH, including chronic hypoxia, monocrotaline toxicity, caveolin-1 knock-out mouse, and the transgenic Ren2 rat which overexpresses the mouse renin gene. Generation of ROS in these models is derived mostly from the activities of the nicotinamide adenine dinucleotide phosphate oxidases, xanthine oxidase, and uncoupled endothelial nitric oxide synthase. As disease progresses circulating monocytes and bone marrow-derived monocytic progenitor cells are attracted to and accumulate in the pulmonary vasculature. Once established, these inflammatory cells generate ROS and secrete mitogenic and fibrogenic cytokines that induce cell proliferation and fibrosis in the vascular wall resulting in progressive vascular remodeling. Deficiencies in antioxidant enzymes also contribute to pulmonary hypertensive states. Current therapies were developed to improve endothelial function, reduce pulmonary artery pressure, and slow the progression of vascular remodeling in the pulmonary vasculature by targeting deficiencies in either NO (PDE-type 5 inhibition) or PGI2 (prostacyclin analogs), or excessive synthesis of ET-1 (ET receptor blockers) with the intent to improve patient clinical status and survival. New therapies may slow disease progression to some extent, but long term management has not been achieved and mortality is still high. Although little is known concerning the effects of current pulmonary arterial hypertension treatments on RV structure and function, interest in this area is increasing. Development of therapeutic strategies that simultaneously target pathology in the pulmonary vasculature and RV may be beneficial in reducing mortality associated with RV failure