Reshma Baliga
Publications
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14.82Impact points
Dietary Nitrate Ameliorates Pulmonary Hypertension: Cytoprotective Role for Endothelial Nitric Oxide Synthase and Xanthine Oxidoreductase.
Circulation. 05/2012;
BACKGROUND: Pulmonary hypertension (PH) is a multi-factorial disease characterized by increased pulmonary vascular resistance and right ventricular failure; morbidity and mortality remain unacceptably high. Loss of nitric oxide (NO) bioactivity is thought to contribute to the pathogenesis of PH and ... [more] BACKGROUND: Pulmonary hypertension (PH) is a multi-factorial disease characterized by increased pulmonary vascular resistance and right ventricular failure; morbidity and mortality remain unacceptably high. Loss of nitric oxide (NO) bioactivity is thought to contribute to the pathogenesis of PH and agents that augment pulmonary NO signaling are clinically effective in the disease. Inorganic nitrate (NO(3)-) and nitrite (NO(2)-) elicit a reduction in systemic blood pressure in healthy individuals; this effect is underpinned by endogenous and sequential reduction to NO. Herein, we determined whether dietary nitrate and nitrite might be preferentially reduced to NO by the hypoxia associated with PH, and thereby offer a convenient, inexpensive method of supplementing NO functionality to reduce disease severity. METHODS AND RESULTS: Dietary nitrate reduced the right ventricular pressure and hypertrophy, and pulmonary vascular re-modeling, in wild-type mice exposed to 3 weeks hypoxia; this beneficial activity was mirrored largely by dietary nitrite. The cytoprotective effects of dietary nitrate were associated with increased plasma & lung concentrations of nitrite and cGMP. The beneficial effects of dietary nitrate and nitrite were reduced in mice lacking endothelial NO synthase (eNOS) or treated with the xanthine oxidoreductase (XOR) inhibitor allopurinol. CONCLUSIONS: These data demonstrate that dietary nitrate, and to a lesser extent dietary nitrite, elicit pulmonary dilatation, prevent pulmonary vascular remodeling, and reduce the RVH characteristic of PH. This favorable pharmacodynamic profile is dependent on eNOS and XOR -catalyzed reduction of nitrite to NO. Exploitation of this mechanism (i.e. dietary nitrate/nitrite supplementation) represents a viable, orally-active therapy for PH.
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5.80Impact points
Mitogen-activated protein kinase phosphatase-1 inhibits myocardial TNF-α expression and improves cardiac function during endotoxemia.
Cardiovascular research. 12/2011; 93(3):471-9.
Myocardial tumour necrosis factor-α (TNF-α) expression induces cardiac dysfunction in endotoxemia. The aim of this study was to investigate the role of mitogen-activated protein kinase phosphatase-1 (MKP1) pathway in myocardial TNF-α expression and cardiac function during endotoxemia. Lipopolysaccha... [more] Myocardial tumour necrosis factor-α (TNF-α) expression induces cardiac dysfunction in endotoxemia. The aim of this study was to investigate the role of mitogen-activated protein kinase phosphatase-1 (MKP1) pathway in myocardial TNF-α expression and cardiac function during endotoxemia. Lipopolysaccharide (LPS) increased MKP1 expression in the myocardium in vivo and in cultured neonatal cardiomyocytes in vitro. LPS-induced extracellular signal-regulated kinase (ERK) 1/2 and p38 phosphorylation in the myocardium was prolonged in MKP1(-/-) mice. Myocardial TNF-α mRNA and protein levels were enhanced in MKP1(-/-) compared with wild-type (WT) mice in endotoxemia, leading to a further decrease in cardiac function. To study if Rac1/p21-activated kinase 1 (PAK1) signalling regulates MKP1 expression, cardiomyocytes were treated with LPS. Inhibition of Rac1 and PAK1 by a dominant negative Rac1 adenovirus (Ad-Rac1N17) and PAK1 siRNA, respectively, blocked LPS-induced MKP1 expression in cardiomyocytes. PAK1 siRNA also decreased p38 and c-Jun N-terminal kinase (JNK) activation, and TNF-α expression induced by LPS. Furthermore, deficiency in either Rac1 or JNK1 decreased myocardial MKP1 expression in endotoxemic mice. LPS activates the Rac1/PAK1 pathway, which increases myocardial MKP1 expression via JNK1. MKP1 attenuates ERK1/2 and p38 activation, inhibits myocardial TNF-α expression, and improves cardiac function in endotoxemia. Thus, MKP1 represents an important negative feedback mechanism limiting pro-inflammatory response in the heart during sepsis.
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5.20Impact points
New perspectives for the treatment of pulmonary hypertension.
British journal of pharmacology. 12/2010; 163(1):125-40.
Pulmonary hypertension (PH) is a debilitating disease with a poor prognosis. Therapeutic options remain limited despite the introduction of prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase 5 inhibitors within the last 15 years; these interventions address predominantly t... [more] Pulmonary hypertension (PH) is a debilitating disease with a poor prognosis. Therapeutic options remain limited despite the introduction of prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase 5 inhibitors within the last 15 years; these interventions address predominantly the endothelial and vascular dysfunctionS associated with the condition, but simply delay progression of the disease rather than offer a cure. In an attempt to improve efficacy, emerging approaches have focused on targeting the pro-proliferative phenotype that underpins the pulmonary vascular remodelling in the lung and contributes to the impaired circulation and right heart failure. Many novel targets have been investigated and validated in animal models of PH, including modulation of guanylate cyclases, phosphodiesterases, tyrosine kinases, Rho kinase, bone morphogenetic proteins signalling, 5-HT, peroxisome proliferator activator receptors and ion channels. In addition, there is hope that combinations of such treatments, harnessing and optimizing vasodilator and anti-proliferative properties, will provide a further, possibly synergistic, increase in efficacy; therapies directed at the right heart may also offer an additional benefit. This overview highlights current therapeutic options, promising new therapies, and provides the rationale for a combination approach to treat the disease.
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5.20Impact points
Resistance to endotoxic shock in mice lacking natriuretic peptide receptor-A.
British journal of pharmacology. 08/2010; 160(8):2045-54.
Excessive production of nitric oxide (NO) by inducible NO synthase (iNOS) is thought to underlie the vascular dysfunction, systemic hypotension and organ failure that characterize endotoxic shock. Plasma levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuret... [more] Excessive production of nitric oxide (NO) by inducible NO synthase (iNOS) is thought to underlie the vascular dysfunction, systemic hypotension and organ failure that characterize endotoxic shock. Plasma levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) are raised in animal models and humans with endotoxic shock and correlate with the associated cardiovascular dysfunction. Since both NO and natriuretic peptides play important roles in cardiovascular homeostasis via activation of guanylate cyclase-linked receptors, we used mice lacking natriuretic peptide receptor (NPR)-A (NPR1) to establish if natriuretic peptides contribute to the cardiovascular dysfunction present in endotoxic shock. Wild-type (WT) and NPR-A knockout (KO) mice were exposed to lipopolysaccharide (LPS) and vascular dysfunction (in vitro and in vivo), production of pro-inflammatory cytokines, and iNOS expression and activity were evaluated. LPS-treated WT animals exhibited a marked fall in mean arterial blood pressure (MABP) whereas NPR-A KO mice maintained MABP throughout. LPS administration caused a greater suppression of vascular responses to the thromboxane-mimetic U46619, ANP, acetylcholine and the NO-donor spermine-NONOate in WT versus NPR-A KO mice. This differential effect on vascular function was paralleled by reduced pro-inflammatory cytokine production, iNOS expression and activity (plasma [NO(x)] and cyclic GMP). These observations suggest that NPR-A activation by natriuretic peptides facilitates iNOS expression and contributes to the vascular dysfunction characteristic of endotoxic shock. Pharmacological interventions that target the natriuretic peptide system may represent a novel approach to treat this life-threatening condition.
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3.71Impact points
Decreased cardiac expression of vascular endothelial growth factor and redox imbalance in murine diabetic cardiomyopathy.
American journal of physiology. Heart and circulatory physiology. 07/2009;
Type I diabetes is associated with a unique form of cardiomyopathy that is present without atherosclerosis. Redox imbalance and/or changes in vascular endothelial growth factor (VEGF) expression have been associated with diabetes-related cardiomyopathy. However, the mechanisms of these changes and t... [more] Type I diabetes is associated with a unique form of cardiomyopathy that is present without atherosclerosis. Redox imbalance and/or changes in vascular endothelial growth factor (VEGF) expression have been associated with diabetes-related cardiomyopathy. However, the mechanisms of these changes and their inter-relationships remain unclear. Using a murine type 1 diabetes model, we tested the hypothesis that alterations in cardiac performance are associated with decreased cardiac microvascular prevalence as well as down regulation of VEGF isoforms. We also investigated oxidative stress as a contributor to regulate individual VEGF isoforms and microvascular rarefaction. Significant and rapid hyperglycemia was observed at 1week post-streptozotocin (STZ) and persisted throughout the 5 week study. Left ventricular (LV) fractional shortening (FS%) was reduced at week 1 and 5 post STZ insult relative to age-matched controls. We also observed the early reduction in E/A ratio at 1 week. Immunostaining for CD31 and digital image analysis demonstrated a 35% reduction in microvessels/myocardial area, indicative of rarefaction, which was highly correlated with FS%. Further, a significant increase in the prevalence of protein-3nitrotyrosine was observed in the diabetic cardiac tissue, which was inversely associated with microvascular rarefaction. The expressions of three VEGF isoforms were significantly reduced to different extents. The reduction of VEGF164 was associated with GSSG accumulation. These data demonstrate that the mouse model of STZ-induced diabetes has hallmark features observed in humans with respect to non-ischemic systolic and diastolic performance and microvascular rarefaction, which are associated with changes in VEGF isoform expression and redox imbalance in the myocardium. Key words: Diabetes, Microvascular density, VEGF, Cardiomyopathy.
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Manipulating the natriuretic peptide system for the treatment of pulmonary hypertension
BMC Pharmacology. 01/2009;
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2.04Impact points
Vasoprotective endothelial effects of a standardized grape product in humans.
Vascular pharmacology. 09/2008;
The pathogenesis of coronary lesion development is a multi-factorial process involving a number of different cell types and covariates, and injury and dysfunction of the vascular endothelium is an important marker and likely participant in the initiation and/or progression of most forms of heart dis... [more] The pathogenesis of coronary lesion development is a multi-factorial process involving a number of different cell types and covariates, and injury and dysfunction of the vascular endothelium is an important marker and likely participant in the initiation and/or progression of most forms of heart disease. In addition to chronic dysfunction of endothelial responses in patients with established heart disease, there is evidence that 'acute insults' can cause measurable dysfunction in vascular response in humans (drug toxicities, hypoxia, high fat meal). Such repeated acute insults may contribute to disease risk in otherwise healthy individuals or promote disease progression in established patients. Consumption of grape products, especially wine, has been linked to lower cardiovascular risk but the vascular endothelial effects of grape products in healthy normal subjects, in the absence of ethanol, have not been evaluated. We therefore tested the hypotheses that 1) a standardized product derived from fresh grapes (GP, acute and chronic consumption) improves endothelial performance in healthy normal young subjects, and 2) that concomitant grape consumption affects the 'acute endothelial insult' caused by a single standardized high fat meal (HF). Acute consumption of GP equivalent to 1.25 cups of fresh grapes caused significant improvement in brachial artery flow mediated dilation (FMD) within 3 h of consumption, when compared to control consumption of sugar solution (p<0.05). No acute changes in heart rate, hemodynamics, or lipid profiles were observed. When this 'dose' was then consumed twice daily for 3 weeks FMD was further improved and total antioxidant capacity in plasma was slightly increased (p<0.05), with no change in heart rate, hemodynamics, or lipid profiles. A single HF meal (900 cal, 49 g total fat) caused a 50% reduction in FMD response when consumed alone, and this effect coincided with increased blood triglyceride levels within 3 h post-consumption. In contrast the concomitant consumption of GP with the HF meal completely prevented this HF-induced vascular endothelial dysfunction (p<0.05), but had no effect on rising triglycerides. These data demonstrate that a modest intake of fresh grapes can have acute favorable effects on vascular endothelial function in normal healthy subjects, that chronic intake can further improve performance and concomitant intake can blunt the 'acute insult' to endothelium caused by a typical western HF meal. This effect is likely to be related to antioxidant effects at the endothelium, rather than changes in blood lipids. These data support epidemiological data of the health benefits of grapes, and demonstrate that 'favorable' food consumption can apparently reduce some toxicities induced by 'unfavorable' food consumption.
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10.69Impact points
Synergy Between Natriuretic Peptides and PDE5 Inhibitors Ameliorates Pulmonary Arterial Hypertension.
American journal of respiratory and critical care medicine. 09/2008;
Rationale/ OBJECTIVES: Phosphodiesterase (PDE) 5 inhibitors (e.g. Sildenafil) are selective pulmonary vasodilators in patients with pulmonary arterial hypertension (PAH). The mechanism(s) underlying this specificity remains unclear, but studies in genetically-modified animals intimate it might be de... [more] Rationale/ OBJECTIVES: Phosphodiesterase (PDE) 5 inhibitors (e.g. Sildenafil) are selective pulmonary vasodilators in patients with pulmonary arterial hypertension (PAH). The mechanism(s) underlying this specificity remains unclear, but studies in genetically-modified animals intimate it might be dependent on natriuretic peptide bioactivity. Herein, we explored the interaction between PDE5 inhibitors and the natriuretic peptide system in vitro and in vivo, including an animal model of PH, to elucidate the (patho)physiological relationship between these two cGMP-regulating systems and potential of a combination therapy exploiting these cooperative pathways. Methods/ MAIN RESULTS: In vitro pharmacological studies using rat vascular tissue revealed that Sildenafil augments vasodilator responses to nitric oxide (NO) in both pulmonary and systemic conduit and resistance arteries whereas identical relaxant responses to ANP are enhanced only in pulmonary vessels. This differential activity was mirrored in vivo where Sildenafil increases the hypotensive actions of ANP in the pulmonary, but not systemic, vasculature. In an animal model of (hypoxia-induced) PH, combination treatment with Sildenafil plus the neutral endopeptidase (NEP) inhibitor Ecadotril (increases endogenous natriuretic peptide levels) acted synergistically, in a cGMP-dependent manner, to reduce many indices of disease severity (e.g. pulmonary artery pressure, right ventricular hypertrophy and pulmonary vascular re-modeling) without significantly affecting systemic blood pressure. CONCLUSIONS: These data demonstrate that PDE5 is a key regulator of cyclic GMP (cGMP)-mediated vasodilatation by ANP in the pulmonary, but not systemic, vasculature, thereby explaining the pulmonary-selectivity of PDE5 inhibitors. Furthermore, exploitation of this mechanism (i.e. PDE5 and NEP inhibition) represents a novel, orally-active combination therapy for PAH.
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5.33Impact points
Characterization of the Human {alpha}1{beta}1 Soluble Guanylyl Cyclase Promoter: KEY ROLE FOR NF-{kappa}B(p50) AND CCAAT-BINDING FACTORS IN REGULATING EXPRESSION OF THE NITRIC OXIDE RECEPTOR.
The Journal of biological chemistry. 08/2008; 283(29):20027-36.
Soluble guanylyl cyclase (sGC) is the principal receptor for NO and plays a ubiquitous role in regulating cellular function. This is exemplified in the cardiovascular system where sGC governs smooth muscle tone and growth, vascular permeability, leukocyte flux, and platelet aggregation. As a consequ... [more] Soluble guanylyl cyclase (sGC) is the principal receptor for NO and plays a ubiquitous role in regulating cellular function. This is exemplified in the cardiovascular system where sGC governs smooth muscle tone and growth, vascular permeability, leukocyte flux, and platelet aggregation. As a consequence, aberrant NO-sGC signaling has been linked to diseases including hypertension, atherosclerosis, and stroke. Despite these key (patho)physiological roles, little is known about the expressional regulation of sGC. To address this deficit, we have characterized the promoter activity of human alpha(1) and beta(1) sGC genes in a cell type relevant to cardiovascular (patho)physiology, primary human aortic smooth muscle cells. Luciferase reporter constructs revealed that the 0.3- and 0.5-kb regions upstream of the transcription start sites were optimal for alpha(1) and beta(1) sGC promoter activity, respectively. Deletion of consensus sites for c-Myb, GAGA, NFAT, NF-kappaB(p50), and CCAAT-binding factor(s) (CCAAT-BF) revealed that these are the principal transcription factors regulating basal sGC expression. In addition, under pro-inflammatory conditions, the effects of the strongest alpha(1) and beta(1) sGC repressors were enhanced, and enzyme expression and activity were reduced; in particular, NF-kappaB(p50) is pivotal in regulating enzyme expression under such conditions. NO itself also elicited a cGMP-independent negative feedback effect on sGC promoter activity that is mediated, in part, via CCAAT-BF activity. In sum, these data provide a systematic characterization of the promoter activity of human sGC alpha(1) and beta(1) subunits and identify key transcription factors that govern subunit expression under basal and pro-inflammatory (i.e. atherogenic) conditions and in the presence of ligand NO.
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5.49Impact points
Bacterial lipopolysaccharide enhances cardiac dysfunction but not retroviral replication in murine AIDS: roles of macrophage infiltration and toll-like receptor 4 expression.
The American journal of pathology. 04/2006; 168(3):727-35.
Cardiovascular disease is an important complication of human immunodeficiency virus/acquired immune deficiency syndrome (AIDS), but the mechanism(s) involved are poorly understood. Although co-infecting pathogens have been implicated as an important factor in AIDS progression, no studies have invest... [more] Cardiovascular disease is an important complication of human immunodeficiency virus/acquired immune deficiency syndrome (AIDS), but the mechanism(s) involved are poorly understood. Although co-infecting pathogens have been implicated as an important factor in AIDS progression, no studies have investigated these interactions in cardiac tissue. We recently demonstrated that the murine AIDS model (LPBM5 retroviral infection) mimics human immunodeficiency virus-related cardiac dysfunction and pathology. We tested the hypothesis that subseptic lipopolysaccharide exposure (LPS) would enhance LPBM5 progression and exacerbate cardiovascular dysfunction during murine AIDS development. LPS (5 mg/kg, Escherichia coli 0111:B4) was administered at 1, 6, and 8 weeks during LPBM5 infection, and cardiac performance was evaluated at 10 weeks using noninvasive echocardiography. LPS alone had no significant effects, whereas it amplified abnormalities in cardiac structure and function observed in murine AIDS. Cardiac dysfunction was associated with selective increases in nonfocal infiltration of CD68(+) cells and correlated with the extent of cardiac dysfunction. Retroviral progression and cardiac retroviral content remained unaltered, but cardiac toll-like receptor 4 was increased in retrovirus + LPS. We provide first-time evidence of multipathogen enhancements to retrovirus-related cardiac complications and implicate innate immune responses, not co-pathogen-induced retroviral replication, as the primary mechanism in this setting.
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14.51Impact points
MAP kinase phosphatase 1 controls innate immune responses and suppresses endotoxic shock.
The Journal of experimental medicine. 02/2006; 203(1):131-40.
Septic shock is a leading cause of morbidity and mortality. However, genetic factors predisposing to septic shock are not fully understood. Excessive production of proinflammatory cytokines, particularly tumor necrosis factor (TNF)-alpha, and the resultant severe hypotension play a central role in t... [more] Septic shock is a leading cause of morbidity and mortality. However, genetic factors predisposing to septic shock are not fully understood. Excessive production of proinflammatory cytokines, particularly tumor necrosis factor (TNF)-alpha, and the resultant severe hypotension play a central role in the pathophysiological process. Mitogen-activated protein (MAP) kinase cascades are crucial in the biosynthesis of proinflammatory cytokines. MAP kinase phosphatase (MKP)-1 is an archetypal member of the dual specificity protein phosphatase family that dephosphorylates MAP kinase. Thus, we hypothesize that knockout of the Mkp-1 gene results in prolonged MAP kinase activation, augmented cytokine production, and increased susceptibility to endotoxic shock. Here, we show that knockout of Mkp-1 substantially sensitizes mice to endotoxic shock induced by lipopolysaccharide (LPS) challenge. We demonstrate that upon LPS challenge, Mkp-1-/- cells exhibit prolonged p38 and c-Jun NH2-terminal kinase activation as well as enhanced TNF-alpha and interleukin (IL)-6 production compared with wild-type cells. After LPS challenge, Mkp-1 knockout mice produce dramatically more TNF-alpha, IL-6, and IL-10 than do wild-type mice. Consequently, Mkp-1 knockout mice develop severe hypotension and multiple organ failure, and exhibit a remarkable increase in mortality. Our studies demonstrate that MKP-1 is a pivotal feedback control regulator of the innate immune responses and plays a critical role in suppressing endotoxin shock.
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3.71Impact points
AIDS-related vasculopathy: evidence for oxidative and inflammatory pathways in murine and human AIDS.
American journal of physiology. Heart and circulatory physiology. 10/2005; 289(4):H1373-80.
Increased life expectancy of human immunodeficiency virus (HIV)-positive patients has led to evidence of complications apparently not directly related to immunodeficiency or opportunistic infection, including increased cardiovascular risk. We tested the hypothesis that vascular dysfunction occurs in... [more] Increased life expectancy of human immunodeficiency virus (HIV)-positive patients has led to evidence of complications apparently not directly related to immunodeficiency or opportunistic infection, including increased cardiovascular risk. We tested the hypothesis that vascular dysfunction occurs in the murine acquired immune deficiency syndrome (AIDS) model and evaluated potential mechanisms in murine AIDS tissues and relevant human HIV/AIDS vascular tissues. We also investigated endothelial activation and/or endothelial protein nitration and their association with time-dependent vascular dysfunction. At 1 and 5 wk of murine AIDS, statistically significant decreases in KCl contractility and time-dependent contractile deficits in response to phenylephrine were observed. The maximal response (E(max)) was reduced by approximately 40% at 10 wk, and EC(50) values were significantly changed: 102 +/- 7.3 ng for control vs. 190 +/- 37 and 130 +/- 22 ng at 5 and 10 wk, respectively (P < 0.05). Endothelium-dependent relaxation to ACh was decreased (EC(50) = 120 +/- 27 and 343 +/- 94 nM for control and at 10 wk, respectively), whereas the response to an exogenous nitric oxide donor, sodium nitroprusside, remained unchanged, suggesting a specific endothelial dysfunction. Histochemical investigations of the same vascular tissues as well as corresponding coronary endothelium showed an increase in protein 3-nitrotyrosine, intercellular adhesion molecule, and nitric oxide synthase isoforms 2 and 3. These findings were corroborated in concurrent experiments in a cohort of well-cataloged human cardiac microvascular tissues. We have demonstrated, for the first time, a specific functional vasculopathy with endothelial involvement in a murine model of AIDS that was also associated with and correlated to increased oxidative stress and specific endothelial activation. This finding was echoed in a relevant population of human HIV/AIDS patients. Research into sources and intracellular targets of oxidants in this disease could provide important mechanistic insights and may reveal new therapeutic opportunities for this increasingly important cardiovascular disease state.
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2.56Impact points
HIV/AIDS-related cardiovascular disease.
Cardiovascular toxicology. 02/2004; 4(3):229-42.
Recent advances in antiretroviral therapies have enhanced survival of HIV/AIDS patients, but cardiovascular complications have emerged as important issues in this growing patient population. Although the antiviral drug therapies apparently yield cardiac and/or vascular toxicities themselves, several... [more] Recent advances in antiretroviral therapies have enhanced survival of HIV/AIDS patients, but cardiovascular complications have emerged as important issues in this growing patient population. Although the antiviral drug therapies apparently yield cardiac and/or vascular toxicities themselves, several other factors associated with HIV pathogenesis have also been implicated. This brief review provides an overview of the significance and complexities of HIV/ AIDS-related cardiovascular complications and addresses some important mechanistic aspects that may contribute to this important clinical problem.
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2.56Impact points
Vascular endothelial toxicity induced by HIV protease inhibitor: evidence of oxidant-related dysfunction and apoptosis.
Cardiovascular toxicology. 02/2004; 4(2):199-206.
HIV-protease inhibitor (HIV-PI) drugs are critical for highly active antiretroviral therapy (HAART) efficacy, but several recent reports have suggested that metabolic and/or cardiovascular toxicities are associated with these drugs. Given the importance of the HIV-PI drug class and the widespread an... [more] HIV-protease inhibitor (HIV-PI) drugs are critical for highly active antiretroviral therapy (HAART) efficacy, but several recent reports have suggested that metabolic and/or cardiovascular toxicities are associated with these drugs. Given the importance of the HIV-PI drug class and the widespread and chronic use of these agents in an expanding patient population, further understanding of this potential drug toxicity is imperative. Here, we investigated a role for direct endothelial toxicity induced by saquinavir (SAQ), the first HIV-PI drug marketed in the United States and still an important component of HAART therapies. In initial studies using isolated vascular tissues, we observed selective impairment of endothelium-dependent vasodilation with no effect on contractile responses. Subsequent studies using human endothelial cells in culture at clinically relevant concentrations (5 and 10 microM, 2-48 h) demonstrated concentration-dependent increases in cell death, mainly via apoptosis rather than necrosis (determined via Annexin-V positive membrane labeling). Live cell imaging also demonstrated increased intracellular oxidant production (as measured by DCF fluorescence), which could be abrogated by incubation with the antioxidant N-acetylcysteine (NAC). NAC also prevented SAQ- induced apoptotic cell death. These data demonstrate that SAQ has direct toxicological effects on endothelial cells, and that the toxicity apparently involves apoptotic pathway activation via reactive oxygen and/or nitrogen species.
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Vasoprotective endothelial effects of a standardized grape product in humans
Vascular Pharmacology.
The pathogenesis of coronary lesion development is a multi-factorial process involving a number of different cell types and covariates, and injury and dysfunction of the vascular endothelium is an important marker and likely participant in the initiation and/or progression of most forms of heart dis... [more] The pathogenesis of coronary lesion development is a multi-factorial process involving a number of different cell types and covariates, and injury and dysfunction of the vascular endothelium is an important marker and likely participant in the initiation and/or progression of most forms of heart disease. In addition to chronic dysfunction of endothelial responses in patients with established heart disease, there is evidence that ‘acute insults’ can cause measurable dysfunction in vascular response in humans (drug toxicities, hypoxia, high fat meal). Such repeated acute insults may contribute to disease risk in otherwise healthy individuals or promote disease progression in established patients. Consumption of grape products, especially wine, has been linked to lower cardiovascular risk but the vascular endothelial effects of grape products in healthy normal subjects, in the absence of ethanol, have not been evaluated. We therefore tested the hypotheses that 1) a standardized product derived from fresh grapes (GP, acute and chronic consumption) improves endothelial performance in healthy normal young subjects, and 2) that concomitant grape consumption affects the ‘acute endothelial insult’ caused by a single standardized high fat meal (HF). Acute consumption of GP equivalent to 1.25 cups of fresh grapes caused significant improvement in brachial artery flow mediated dilation (FMD) within 3 h of consumption, when compared to control consumption of sugar solution (p < 0.05). No acute changes in heart rate, hemodynamics, or lipid profiles were observed. When this ‘dose’ was then consumed twice daily for 3 weeks FMD was further improved and total antioxidant capacity in plasma was slightly increased (p < 0.05), with no change in heart rate, hemodynamics, or lipid profiles. A single HF meal (900 cal, 49 g total fat) caused a 50% reduction in FMD response when consumed alone, and this effect coincided with increased blood triglyceride levels within 3 h post-consumption. In contrast the concomitant consumption of GP with the HF meal completely prevented this HF-induced vascular endothelial dysfunction (p < 0.05), but had no effect on rising triglycerides. These data demonstrate that a modest intake of fresh grapes can have acute favorable effects on vascular endothelial function in normal healthy subjects, that chronic intake can further improve performance and concomitant intake can blunt the ‘acute insult’ to endothelium caused by a typical western HF meal. This effect is likely to be related to antioxidant effects at the endothelium, rather than changes in blood lipids. These data support epidemiological data of the health benefits of grapes, and demonstrate that ‘favorable’ food consumption can apparently reduce some toxicities induced by ‘unfavorable’ food consumption.
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Roles and mechanisms of oxidant stress in cardiovascular disease [electronic resource] /
Abstract: My primary dissertation focus is understanding the pathology behind cardiovascular disease across disease states, in an attempt to provide novel mechanistic insight so that specialized therapy can be developed. Section I: HIV related cardiovascular disease: The first four chapters: HIV-rel... [more] Abstract: My primary dissertation focus is understanding the pathology behind cardiovascular disease across disease states, in an attempt to provide novel mechanistic insight so that specialized therapy can be developed. Section I: HIV related cardiovascular disease: The first four chapters: HIV-related cardiovascular complications represent increasingly important contributors to the overall morbidity and mortality of HIV/AIDS patients. Chapter 2 reviews the emergent field of HIV related vascular abnormalities primarily related to alterations in the vascular endothelium. In Chapter 3, we employed a well-established murine model of retroviral infection (LPBM5 virus) and defined the time-dependencies of retroviral progression and cardiac dysfunction corroborated our findings in human tissues. In chapter 4 we tested the hypothesis that HIV-PI's impose direct detrimental effects on vascular endothelium. Chapter 5 details a role for direct endothelial toxicity induced by Saquinavir (SAQ). Section II deals with cardiovascular complications of diabetes in a mouse model of streptozotocin induced hyperglycemia, a type I diabetes model, studied longitudinally at 0, 1week and 5 weeks post-STZ, for assessment of diastolic and systolic performance by non-invasive echocardiography, and electrocardiographically for conduction abnormalities. We found the STZ mouse model to be appropriate for mechanistic study of Type I diabetic cardiomyopathy, providing time-dependent, clinically relevant assessments of cardiac performance (systolic, diastolic and electrocardiographic) as a foundation for further mechanistic studies, which are shown in chapter 7. Section 3, Chapter 8, appendix A and B: we looked at mechanisms of cardiac dysregulation and development of arrhythmias in canine models. In Appendix A we tested the hypothesis that two models had differing underlying mechanisms of structural remodeling, resulting in development of substrate for AF. Chapter 8, looks in more detail at the MR Dog model, studying development of AF susceptibility over time, to isolate the mechanisms of dysfunction. Finally in Appendix B we tested a novel therapeutic agent, ALT-711 that specifically targets fibrosis stability for its therapeutic value in chronic atrial dilatation (MR) induced AF. Taken together, these studies show that increased oxidative stress is a common factor in cardiovascular dysfunction across disease states, and therapeutic agents targeting oxidative damage might have unique importance to cardiovascular health. Document formatted into pages. Thesis (Ph. D.)--Ohio State University, 2004. Includes bibliographical references. System requirements: World Wide Web browser.
Following (8)
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David L Selwood
University College London -
Beata Wojciak-Stothard
Imperial College London -
Leif D Nelin
Nationwide Children's Hospital -
Melanie Madhani
University of Birmingham -
Lan Zhao
Imperial College London
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