PubMed Health⌕ Search

Biomedical subjects

Marc S Penn

Publications and source records attributed to Marc S Penn.

At least 19 recordsLinked to original sources
PubMed2007

Cell-based gene therapy for the prevention and treatment of cardiac dysfunction.

A substantial need exists for new treatments to prevent and treat cardiac dysfunction. In the 1990s, there was great hope for gene therapy in this regard. Since that time, the focus has switched to cell therapy-in particular, therapy-with the aim of inducing myocardial regeneration. Individually, gene and cell therapies still have substantial promise. Ultimately, however, the convergence of both techniques might be necessary to achieve improvements in cardiac function and more successful clinical outcomes in patients with cardiac dysfunction. This approach has already been adopted for treatment of malignancies. Several gene products are currently being studied, including growth factors and chemokines that can modulate the survival and function of cardiac myocytes following an ischemic event and influence remodeling of the left ventricle. However, several issues remain, including the optimization and characterization of cell types, selection of vectors for gene transfer, and identification of appropriate strategies for delivery. Here, we review the potential and need for cell-based gene therapy for the prevention and treatment of cardiac dysfunction and attempt to discuss the unresolved issues.

Cell Transplantation↗
PubMed2006

Stem cell therapy enhances electrical viability in myocardial infarction.

Clinical studies suggest increased arrhythmia risk associated with cell therapy for myocardial infarction (MI); however, the underlying mechanisms are poorly understood. We hypothesize that the degree of electrical viability in the infarct and border zone associated with skeletal myoblast (SKMB) or mesenchymal stem cell (MSC) therapy will determine arrhythmia vulnerability in the whole heart. Within 24 h of LAD ligation in rats, 2 million intramyocardially injected SKMB (n=6), intravenously infused MSC (n=7), or saline (n=7) was administered. One month after MI, cardiac function was determined and novel optical mapping techniques were used to assess electrical viability and arrhythmia inducibility. Shortening fraction was greater in rats receiving SKMB (17.8%+/-5.3%, p=0.05) or MSC (17.6%+/-3.0%, p<0.01) compared to MI alone (10.1%+/-2.2%). Arrhythmia inducibility score was significantly greater in SKMB (2.8+/-0.2) compared to MI (1.4+/-0.5, p=0.05). Inducibility score for MSC (0.6+/-0.4) was significantly lower than SKMB (p=0.01) and tended to be lower than MI. Optical mapping revealed that MSC therapy preserved electrical viability and impulse propagation in the border zone, but SKMB did not. In addition, injected SKMBs were localized to discrete cell clusters where connexin expression was absent. In contrast, infused MSCs engrafted in a more homogeneous pattern and expressed connexin proteins. Even though both MSC and SKMB therapy improved cardiac function following MI in rat, SKMB therapy significantly increased arrhythmia inducibility while MSC therapy tended to lower inducibility. In addition, only MSC therapy was associated with enhanced electrical viability, diffuse engraftment, and connexin expression, which may explain the differences in arrhythmia inducibility.

Animals↗
PubMed2006

Monocyte chemotactic protein-3 is a myocardial mesenchymal stem cell homing factor.

MSCs have received attention for their therapeutic potential in a number of disease states, including bone formation, diabetes, stem cell engraftment after marrow transplantation, graft-versus-host disease, and heart failure. Despite this diverse interest, the molecular signals regulating MSC trafficking to sites of injury are unclear. MSCs are known to transiently home to the freshly infarcted myocardium. To identify MSC homing factors, we determined chemokine expression pattern as a function of time after myocardial infarction (MI). We merged these profiles with chemokine receptors expressed on MSCs but not cardiac fibroblasts, which do not home after MI. This analysis identified monocyte chemotactic protein-3 (MCP-3) as a potential MSC homing factor. Overexpression of MCP-3 1 month after MI restored MSC homing to the heart. After serial infusions of MSCs, cardiac function improved in MCP-3-expressing hearts (88.7%, p < .001) but not in control hearts (8.6%, p = .47). MSC engraftment was not associated with differentiation into cardiac myocytes. Rather, MSC engraftment appeared to result in recruitment of myofibroblasts and remodeling of the collagen matrix. These data indicate that MCP-3 is an MSC homing factor; local overexpression of MCP-3 recruits MSCs to sites of injured tissue and improves cardiac remodeling independent of cardiac myocyte regeneration.

Animals↗
PubMed2006

Scaling of diastolic intraventricular pressure gradients is related to filling time duration.

In early diastole, pressure is lower in the apex than in the base of the left ventricle (LV). This early intraventricular pressure difference (IVPD) facilitates LV filling. We assessed how LV diastolic IVPD and intraventricular pressure gradient (IVPG), defined as IVPD divided by length, scale to the heart size and other physiological variables. We studied 10 mice, 10 rats, 5 rabbits, 12 dogs, and 21 humans by echocardiography. Color Doppler M-mode data were postprocessed to reconstruct IVPD and IVPG. Normalized LV filling time was calculated by dividing filling time by RR interval. The relationship between IVPD, IVPG, normalized LV filling time, and LV end-diastolic volume (or mass) as fit to the general scaling equation Y = kM beta, where M is LV heart size parameter, Y is a dependent variable, k is a constant, and beta is the power of the scaling exponent. LV mass varied from 0.049 to 194 g, whereas end-diastolic volume varied from 0.011 to 149 ml. The beta values relating normalized LV filling time with LV mass and end-diastolic volume were 0.091 (SD 0.011) and 0.083 (SD 0.009), respectively (P < 0.0001 vs. 0 for both). The beta values relating IVPD with LV mass and end-diastolic volume were similarly significant at 0.271 (SD 0.039) and 0.243 (SD 0.0361), respectively (P < 0.0001 vs. 0 for both). Finally, beta values relating IVPG with LV mass and end-diastolic volume were -0.118 (SD 0.013) and -0.104 (SD 0.011), respectively (P < 0.0001 vs. 0 for both). As a result, there was an inverse relationship between IVPG and normalized LV filling time (r = -0.65, P < 0.001). We conclude that IVPD decrease, while IVPG increase with decreasing animal size. High IVPG in small mammals may be an adaptive mechanism to short filling times.

Adult↗
PubMed2006

The effects of oral Cardax (disodium disuccinate astaxanthin) on multiple independent oxidative stress markers in a mouse peritoneal inflammation model: influence on 5-lipoxygenase in vitro and in vivo.

Disodium disuccinate astaxanthin ('rac'-dAST; Cardax) is a water-dispersible C40 carotenoid derivative under development for oral and parenteral administration for cardioprotection of the at-risk ischemic cardiovascular patient. In experimental infarction models in animals (rats, rabbits, and dogs), significant myocardial salvage has been obtained, up to 100% at the appropriate dose in dogs. The documented mechanism of action in vitro includes direct scavenging of biologically produced superoxide anion; in vivo in rabbits, modulation of the complement activity of serum has also been shown. A direct correlation between administration of the test compound in animals and reductions of multiple, independent markers of oxidative stress in serum was recently obtained in a rat experimental infarction model. For the current study, it was hypothesized that oral Cardax administration would inhibit oxidative damage of multiple relevant biological targets in a representative, well-characterized murine peritoneal inflammation model. A previously developed mass spectrometry-based (LC/ESI/MS/MS) approach was used to interrogate multiple distinct pathways of oxidation in a black mouse (C57/BL6) model system. In vivo markers of oxidant stress from peritoneal lavage samples (supernatants) were evaluated in mice on day eight (8) after treatment with either Cardax or vehicle (lipophilic emulsion without drug) orally by gavage at 500 mg/kg once per day for seven (7) days at five (5) time points: (1) baseline prior to treatment (t=0); (2) 16 h following intraperitoneal (i.p.) injection with thioglycollate to elicit a neutrophilic infiltrate; (3) 4 h following i.p. injection of yeast cell wall (zymosan; t=16 h/4 h thioglycollate+zymosan); (4) 72 h following i.p. injection with thioglycollate to elicit monocyte/macrophage infiltration; and (5) 72 h/4 h thioglycollate+zymosan. A statistically significant sparing effect on the arachidonic acid (AA) and linoleic acid (LA) substrates was observed at time points two and five. When normalized to the concentration of the oxidative substrates, statistically significant reductions of 8-isoprostane-F(2alpha) (8-iso-F(2alpha)) at time point three (maximal neutrophil recruitment/activation), and 5-HETE, 5-oxo-EET, 11-HETE, 9-HODE, and PGF(2alpha) at time point five (maximal monocyte/macrophage recruitment/activation) were observed. Subsequently, the direct interaction of the optically inactive stereoisomer of Cardax (meso-dAST) with human 5-lipoxygenase (5-LOX) was evaluated in vitro with circular dichroism (CD) and electronic absorption (UV/Vis) spectroscopy, and subsequent molecular docking calculations were made using mammalian 15-LOX as a surrogate (for which XRC data has been reported). The results suggested that the meso-compound was capable of interaction with, and binding to, the solvent-exposed surface of the enzyme. These preliminary studies provide the foundation for more detailed evaluation of the therapeutic effects of this compound on the 5-LOX enzyme, important in chronic diseases such as atherosclerosis, asthma, and prostate cancer in humans.

Animals↗
PubMed2006

Granulocyte colony stimulating factor in patients with large acute myocardial infarction: results of a pilot dose-escalation randomized trial.

BACKGROUND: Preclinical studies suggest that administration of cytokines to mobilize stem cells and alter the postinfarction inflammatory cardiac milieu may enhance left ventricular function and survival. METHODS: Eighteen patients were randomized in a 2:1 double-blind fashion to granulocyte colony stimulating factor (G-CSF) (at 5 escalating to 10 microg/kg per day subcutaneously for 5 days [6 patients in each group]) or matching placebo. Principal safety and efficacy end points were rupture-free survival and recovery of left ventricular function, respectively. Mobilization into the systemic circulation of precursor CD34+ and CD117+ stem cells at 30 days were also assessed. RESULTS: Baseline characteristics of the 3 groups were well matched. Mean +/- SD creatine kinase-MB maximum was 349 (169) IU. Follow-up averaged 30 +/- 6, 21 +/- 11, and 11 +/- 6 months in the 3 groups, respectively. Precursor cell mobilization increased by a factor of 5 to 7 in the G-CSF-treated patients. There were no deaths or myocardial ruptures leading to tamponade through 30 days. Baseline and 30-day left ventricular ejection fraction in the placebo, 5-microg, and 10-microg dose groups were 33.7% (1.6) and 41.7% (8.2), 36.8% (7.5) and 41.3% (10.3), and 33.5% (4.8) and 38.7% (7.3), respectively (P = NS for all between-group comparisons). No differences between the G-CSF and placebo groups were noted in any other measure of left ventricular systolic or diastolic function 30 days after infarction. CONCLUSIONS: Despite demonstrated mobilization of precursor stem cells in a timely fashion, in this small, pilot-scale randomized trial involving patients with large myocardial infarction, we were unable to demonstrate improvement in left ventricular function at 30 days.

Aged↗
PubMed2006

Mechanical and electrical effects of cell-based gene therapy for ischemic cardiomyopathy are independent.

Cell-based gene therapy to alter the myocardial tissue microenvironment has been shown to improve mechanical cardiac function, but little is known regarding its effects on arrhythmogenic risk. Clinical studies with skeletal myoblasts (SKMBs) have suggested a potential increase in arrhythmogenic risk. Therefore, we studied the functional mechanical and electrical effects of transient reestablishment of stem cell homing via transplantation of stromal-cell derived factor-1 (SDF-1)-expressing SKMBs. Eight weeks after anterior myocardial infarction, rats received in five divided doses into the periinfarct zone 1 million SKMBs transfected with AdSDF-1 (n=15) or AdGFP (n=8). Echocardiography was used to quantify changes in cardiac function, and optical mapping was used to determine the arrhythmogenic risk. Eight weeks after cell therapy, we observed a 54% (p=0.004) increase in shortening fraction in AdSDF-1:SKMB-treated rats, but only an 18.8% increase (p=not significant) with GFP:SKMB. SDF-1-treated hearts exhibited an increase in vascular density compared with control SKMBs (34.9+/-7.1 vs. 20.7+/-5.6 vessels/mm2; p<0.01). Optical mapping performed 8 weeks after cell therapy revealed that all animals that received SKMBs regardless of viral transfection had inducible ventricular tachycardia (VT) whereas only 50% of saline-treated animals had inducible VT (p<0.05). Transient reestablishment of stem cell homing via transplantation of modified SKMBs is sufficient to improve cardiac function. However, despite improved mechanical function, the risk of ventricular tachycardia increased. We propose that future studies on functional effects of cell-based gene therapies should address both mechanical and electrical consequences.

Adenoviridae↗
PubMed2006

Stem cells in cardiovascular disease: methods and protocols.

Stem cells are cells capable of proliferation, self-renewal, and differentiation into various organ-specific cell types. Stem cells are subclassified based on their species of origin (mice, rat, human), developmental stage of the species (embryonic, fetal, or adult), tissue of origin (hematopoietic, mesenchymal, skeletal, neural), and potential to differentiate into one or more specific types of mature cells (totipotent, pluripotent, multipotent). Embryonic stem (ES) cells are totipotent, primitive cells derived from the embryo that have the potential to become all specialized cell types. Conversely, adult stem cells are undifferentiated cells found in differentiated tissue that retain the potential to renew themselves and differentiate to yield organ-specific tissues. Stem cells are attractive candidates for novel therapeutics for patients with different heart diseases, including congestive heart failure, most commonly caused by myocardial infarction. The remarkable proliferative and differentiation capacity of stem cells promises an almost unlimited supply of specific cell types including viable functioning cardiomyocytes to replace the scarred myocardium following transplantation.

Arrhythmias, Cardiac↗
PubMed2006

Engineered cell therapy for sustained local myocardial delivery of nonsecreted proteins.

Novel strategies for the treatment of congestive heart failure have taken the form of gene and cell therapy to induce angiogenesis, optimize calcium handling by cardiac myocytes, or regenerate damaged myocardial tissue. Arguably both gene- and cell-based therapies would be benefited by having the ability to locally deliver specific transcription factors and other usually nonsecreted proteins to cells in the surrounding myocardial tissue. The herpes simplex virus type 1 (HSV-1) tegument protein VP22 has been shown to mediate protein intercellular trafficking to mammalian cells and finally localize into the nucleus, which makes it a useful cargo-carrying functional protein in cell-based gene therapy. While VP22 has been studied as a means to modulate tumor growth, little is known about the distribution and transport kinetics of VP22 in the heart and its potential application in combination with autologous cell transplantation for the delivery of proteins to myocardial tissue. The aim of this study was to evaluate the efficacy of VP22 fusion protein intercellular trafficking combined with autologous cell transplantation in the heart. In an in vitro study untransfected rat heart cells were cocultured with stably transfected rat cardiac fibroblasts (RCF) with fusion constructs of VP22. The control experiment was untransfected rat heart cells co-plated with RCF stably transfected with enhanced green fluorescence protein (eGFP). The Lewis rat model was selected for in vivo study. In the in vitro studies there was a 14-fold increase in the number of GFP-positive cells 48 h after initiating coculture with VP22-eGFP RCF compared to eGFP RCF. In the rat model, transplantation of VP22-eGFP expressing RCF led to VP22-eGFP fusion protein delivery to an area of myocardial tissue that was 20-fold greater than that observed when eGFP RCF were transplanted. This area appeared to reach a steady state between 7 and 10 days after transplantation. The VP22-eGFP area consisted of eGFP-positive endothelium, smooth muscle cells, and cardiac myocytes with delivery to an area of approximately 1 mm2 of myocardial tissue. Our data suggest a viable strategy for the delivery of proteins that are not naturally secreted or internalized, and provide the first insight into the feasibility and effectiveness of cell-penetrating proteins combined with cell transplantation in the heart.

Animals↗
PubMed2005

Peroxisome proliferator-activated receptor gamma down-regulates receptor for advanced glycation end products and inhibits smooth muscle cell proliferation in a diabetic and nondiabetic rat carotid artery injury model.

Diabetes is associated with an increase in circulating advanced glycosylation end products (AGEs) and the increased expression of the receptor for AGEs (RAGE). Inhibition of AGE/RAGE binding through the administration of soluble RAGE (sRAGE) has been shown to decrease neointimal hyperplasia. Peroxisome proliferator-activated receptor gamma (PPARgamma), which inhibits neointimal hyperplasia, has been shown to decrease RAGE expression in cultured endothelial cells. We hypothesized that PPARgamma agonists inhibit neointimal hyperplasia via down-regulation of RAGE in vivo. Pretreatment of rat aortic smooth muscle cells (SMCs) with PPARgamma agonist rosiglitazone significantly down-regulated RAGE expression and inhibited SMC proliferation in response to the RAGE agonist S100/calgranulins. In vivo studies showed that rosiglitazone decreased RAGE expression and SMC proliferation at 7 days following carotid arterial injury in both diabetic and nondiabetic rats. At 21 days following injury, neointimal formation was significantly decreased in both diabetic and nondiabetic animals that received rosiglitazone. To determine whether inhibition of neointimal formation by PPARgamma activation could fully be accounted for by its down-regulation of RAGE, we compared the results obtained in animals treated with sRAGE, PPARgamma activator, and sRAGE + PPARgamma activator. Consistent with PPARgamma working through its effects on RAGE, we found that the addition of PPARgamma activator to sRAGE did not result in any further decrease in neointimal formation. These data demonstrate for the first time that PPARgamma agonists inhibit RAGE expression at sites of arterial injury and suggest that down-regulation of RAGE by the PPARgamma activation inhibits neointimal formation in response to arterial injury.

Animals↗
PubMed2005

Myeloperoxidase-generated oxidants modulate left ventricular remodeling but not infarct size after myocardial infarction.

BACKGROUND: Inflammation after myocardial infarction (MI) heralds worse left ventricular (LV) function and clinical outcomes. However, whether inflammation affects LV function by extending myonecrosis and/or altering LV remodeling remains unknown. We hypothesized that cytotoxic aldehydes generated during oxidative stress may adversely affect remodeling and infarct size. One theoretical source of reactive aldehydes is oxidation of common alpha-amino acids by myeloperoxidase (MPO) released by leukocytes. However, a role for MPO in formation of aldehydes in vivo and the functional consequences of MPO-generated oxidants in ischemia/reperfusion models of MI have not been established. METHODS AND RESULTS: In studies with cell types found in vascular tissue, MPO-oxidation products of glycine (formaldehyde) and threonine (acrolein) were the most cytotoxic. Mass spectrometry studies of myocardial tissue from murine models of acute MI (both chronic left anterior descending coronary artery ligation and ischemia/reperfusion injury) confirmed that MPO serves as a major enzymatic source in the generation of these cytotoxic aldehydes. Interestingly, although MPO-null mice experienced 35.1% (P<0.001) less LV dilation and a 52.2% (P<0.0001) improvement in LV function compared with wild-type mice 24 days after ischemia/reperfusion injury, no difference in infarct size between wild-type and MPO-null mice was noted. CONCLUSIONS: The present data separate inflammatory effects on infarct size and LV remodeling and demonstrate that MPO-generated oxidants do not significantly affect tissue necrosis after MI but rather have a profound adverse effect on LV remodeling and function.

Acrolein↗
PubMed2005

Optical mapping of late myocardial infarction in rats.

Late myocardial infarction (MI) is associated with ventricular arrhythmias and sudden cardiac death. The exact mechanistic relationship between abnormal cellular electrophysiology, conduction abnormalities, and arrhythmogenesis associated with late MI is not completely understood. We report a novel, rapid dye superfusion technique to enable whole heart, high-resolution optical mapping of late MI. Optical mapping of action potentials was performed in normal rats and rats with anterior MI 7 days after left anterior descending artery ligation. Hearts from normal rats exhibited normal action potentials and impulse conduction. With the use of programmed stimulation to assess arrhythmia inducibility, 29% of hearts with late MI had inducible sustained ventricular tachycardia, compared with 0% in normal rats. A causal relationship between the site of infarction, abnormal action potential conduction (i.e., block and slow conduction), and arrhythmogenesis was observed. Optical mapping techniques can be used to measure high-resolution action potentials in a whole heart model of late MI. This experimental model reproduces many of the electrophysiological characteristics (i.e., conduction slowing, block, and ventricular tachycardia) associated with MI in patients. Importantly, the results of this study can enhance our ability to understand the interplay between cellular heterogeneity, conduction abnormalities, and arrhythmogenesis associated with MI.

Action Potentials↗
PubMed2005

Alterations in internal elastic lamina permeability as a function of age and anatomical site precede lesion development in apolipoprotein E-null mice.

Early atherosclerosis is characterized by the accumulation of plasma-borne macromolecules (eg, low-density lipoproteins) in the arterial intima, which is bordered by endothelial cells (EC) and the internal elastic lamina (IEL). This accumulation is believed to be secondary to increased EC permeability. We hypothesized that a decrease in IEL permeability may precede lesion development and contribute to macromolecular accumulation. To test this hypothesis, we quantified EC and IEL permeability in lesion-free areas of the thoracic and abdominal aortas of chow-fed C57BL/6 control and atherosclerotic-prone apolipoprotein E (apoE)-null mice at 3 and 5 months of age. Between 3 and 5 months of age, apoE-null mice begin to develop atherosclerotic lesions in the thoracic aorta. No significant differences in EC and IEL permeability were observed at either time in C57BL/6 control mice. In contrast, 78% and 19% decreases in IEL permeability of the thoracic aorta and abdominal aorta, respectively, were observed between 3 to 5 months of age in apoE-null mice (thoracic: 2.05+/-1.33 and 0.44+/-0.15 microm/min, P<0.001; abdominal: 1.13+/-0.58 and 0.93+/-0.44 microm/min, P<0.05). To further determine whether decreased IEL permeability is linked with atherosclerotic lesion development, we quantified IEL permeability in the greater and lesser curvature of the aortic arch. In apoE-null mice, the lesser curvature of the aortic arch develops lesions before the greater curvature. We found a significant and sustained decrease (59%) in IEL permeability in the lesser curvature of the aortic arch compared with the greater curvature. These data suggest that atherogenesis involves the pathological remodeling of the IEL, not the endothelium before lesion development. This remodeling may be attributable to local responses of the endothelium and smooth muscle cells to hyperlipidemia.

Age Factors↗
PubMed2005

Differences in left ventricular long-axis function from mice to humans follow allometric scaling to ventricular size.

While the heart size maintains a constant proportion to body size, heart function parameters, such as heart rate and cardiac output, show a more complex scaling pattern. How these phenomena affect the long-axis left ventricular (LV) function is unknown. We studied 10 mice, 15 rats, 6 rabbits, 8 mongrel dogs and 38 human volunteers. Doppler tissue echocardiography data were postprocessed to reconstruct mitral annulus (MA) peak systolic velocity and displacement. The relationship between MA peak velocity, MA displacement and LV ejection time, and LV end-diastolic volume (and mass) were fit to an allometric (power-law) equation Y=kMbeta. LV mass varied from 0.062 to 255 g, while end-diastolic volume varied from 0.014 to 205 ml. beta values of the relation between LV ejection time and LV end-diastolic volume and mass were 0.247+/-0.017 and 0.267+/-0.018, respectively. beta values of the relationship between MA displacement and LV end-diastolic volume and mass were 0.358+/-0.047 and 0.390+/-0.051 (P<0.023 versus beta of LV ejection time). beta values of the relationship between MA peak systolic velocity and LV end-diastolic volume and mass were 0.096+/-0.012 and 0.100+/-0.013, respectively (P<0.0001 versus 0). Finally, beta values of the relationship between the long-to-short axis displacement ratio and LV end-diastolic volume and mass were 0.077+/-0.017 and 0.086+/-0.019 (P<0.0001 versus 0). We conclude that MA velocity, displacement, and long-to-short axis displacement ratio scale allometrically to heart size. This reduces the relative long-axis contribution to heart function in small mammals.

Animals↗
PubMed2005

Platelet, not endothelial, P-selectin is required for neointimal formation after vascular injury.

BACKGROUND: P-selectin blockade significantly inhibits inflammation and neointimal formation after arterial injury; however, the independent roles of platelet and endothelial P-selectins in this process are unknown. In atherosclerosis, both platelet and endothelial cell P-selectins are important. This study was designed to determine whether P-selectin expression on platelet, endothelial, or both surfaces is critical to the inflammatory response and neointimal formation after arterial injury. METHODS AND RESULTS: Using wild-type (WT) and P-selectin-knockout (Psel(-/-)) mice, we performed bone marrow transplantation to generate chimeric mice that expressed either platelet P-selectin (Plt-Psel) or endothelial P-selectin (EC-Psel). Double injury of the carotid artery was performed in these mice as well as in WT and Psel(-/-) mice. Animals were euthanized 4 or 21 days after arterial injury. Morphometric data showed that there was more neointimal formation in the WT mouse group when compared with the Psel(-/-) mouse group (0.015+/-0.004 vs 0.004+/-0.004 mm2, P<0.001). Further comparison showed significantly less neointimal area in EC-Psel mice (0.006+/-0.004 mm2) compared with Plt-Psel mice (0.011+/-0.005 mm2, P=0.026) and WT mice (0.015+/-0.004 mm2, P=0.001). No significant differences were observed between WT and Plt-Psel mice or between Psel(-/-) and EC-Psel mice. Decreased neointimal formation was accompanied by a reduced inflammatory response, as evidenced by immunostaining of RANTES and MCP-1 4 days after injury. CONCLUSIONS: Platelet P-selectin expression, but not endothelial P-selectin, plays a crucial role in the development of neointimal formation after arterial injury, and therapeutic strategies targeting leukocyte-platelet interactions could be effective in inhibiting restenosis.

Angioplasty, Balloon↗
PubMed2005

Carnitine palmitoyl transferase-I inhibition prevents ventricular remodeling and delays decompensation in pacing-induced heart failure.

OBJECTIVE: Experimental evidence suggests that modulation of myocardial substrate metabolism can markedly affect the progression of chronic heart failure (HF). We tested whether the inhibition of carnitine palmitoyl transferase-I (CPT-I), the enzyme regulating mitochondrial fatty acid oxidation, slows left ventricular remodeling and deterioration of function in pacing-induced HF. METHODS: Normal dogs (n=9) were compared to untreated dogs with pacing-induced HF (n=9) and HF dogs treated with 65 mg/kg/day of oxfenicine (HF+Oxf, n=9), a CPT-I inhibitor. RESULTS: HF+Oxf reached terminal failure (LV end-diastolic pressure=25 mm Hg) 6 days later than untreated HF (P<0.05). At 28 days of pacing, hemodynamic alterations and LV dilation were significantly attenuated and the 25% decrease in LV wall thickness was completely prevented in HF+Oxf vs. untreated HF, as was the activation of matrix metalloproteinase-2 and -9, markers of tissue remodeling. Oxfenicine also prevented HF-induced transcriptional down-regulation of CPT-I, medium chain acyl-CoA dehydrogenase, GAPDH and citrate synthase, key enzymes of cardiac energy metabolism. In addition, mRNA, but not protein levels of the nuclear receptor peroxisome proliferator-activated receptor-alpha were reduced in untreated HF, while they did not change significantly in HF+Oxf, as compared to control. CONCLUSIONS: CPT-I inhibition early in the development of HF prevented LV wall thinning and delayed the time to end-stage failure. While these results are limited to an experimental model of disease, they nevertheless suggest that CPT-I inhibition might be effective for slowing the progression of clinical HF.

Animals↗