Biomedical subjects

Kenneth Walsh

Publications and source records attributed to Kenneth Walsh.

At least 73 records · Page 4Linked to original sources

PubMed2003

Endothelial cell overexpression of fas ligand attenuates ischemia-reperfusion injury in the heart.

Fas ligand (FasL) is a member of tumor necrosis factor family that induces apoptosis in target cells that express Fas. The function of FasL during inflammation remains controversial. In this study, we examined the role of vascular endothelial FasL during acute myocardial ischemia-reperfusion that is closely associated with inflammation. Transgenic mouse lines were established that overexpress human FasL on endothelium under the control of the vascular endothelial cadherin promoter. Expression of FasL transgene was detected at both mRNA and protein levels, and functional transgene-encoded FasL protein was specifically expressed on the surface of vascular endothelial cells. Transgenic mice developed normally and had normal hearts. When subjected to 30 min of myocardial ischemia and 72 h of reperfusion, myocardial infarct size was reduced by 42% in the transgenic mice compared with nontransgenic littermates (p < 0.05). Moreover, hemodynamic data demonstrated that transgenic hearts performed better following ischemia and reperfusion compared with nontransgenic hearts. Myocardial neutrophil infiltration was reduced by 54% after 6 h of reperfusion in transgenic hearts (p < 0.01). Neutrophil depletion prior to ischemia-reperfusion injury led to smaller infarcts that were not different between transgenic and nontransgenic mice, suggesting that endothelial FasL may attenuate ischemia-reperfusion injury by abating the inflammatory response. These results indicate that vascular endothelial FasL may exert potent anti-inflammatory actions in the setting of myocardial ischemia-reperfusion injury.

Animals↗

PubMed2003

IL-6 and matrix metalloproteinase-1 are regulated by the cyclin-dependent kinase inhibitor p21 in synovial fibroblasts.

During the pathogenesis of rheumatoid arthritis (RA), the synovial fibroblasts increase in number and produce proinflammatory cytokines and matrix metalloproteinases (MMPs) that function to promote inflammation and joint destruction. Recent investigations have suggested that cell cycle activity and inflammation may be linked. However, little is known about the mechanisms responsible for the coordinate regulation of proliferation and the expression of proinflammatory molecules in RA synovial fibroblasts. Here, we demonstrate a 50 +/- 10% decrease in the expression of p21, a cell cycle inhibitor, in the synovial fibroblast population from RA compared with osteoarthritis (OA) synovial tissue. Moreover, p21 positivity in the synovial fibroblasts inversely correlates with medium synovial lining thickness (r = -0.76; p < 0.02). The expression of p21 is also reduced in isolated RA synovial fibroblasts compared with OA synovial fibroblasts. Adenovirus-mediated delivery of p21 (Ad-p21) arrests both RA and OA synovial fibroblasts in the G(0)/G(1) phase of the cell cycle without inducing cytotoxicity. However, the spontaneous production of IL-6 and MMP-1 is suppressed only in the Ad-p21-infected RA synovial fibroblasts, indicating a novel role for p21 in RA. Analyses of p21-deficient mouse synovial fibroblasts reveal a 100-fold increase in IL-6 protein and enhance IL-6 and MMP-3 mRNA. Restoration of p21, but not overexpression of Rb, which also induces G(0)/G(1) cell cycle arrest, decreases IL-6 synthesis in p21-null synovial fibroblasts. Furthermore, in RA synovial fibroblasts the ectopic expression of p21 reduces activation of the AP-1 transcription factor. Additionally, p21-null synovial fibroblasts display enhanced activation of AP-1 compared with wild-type synovial fibroblasts. These data suggest that alterations in p21 expression may activate AP-1 leading to enhanced proinflammatory cytokine and MMP production and development of autoimmune disease.

Adenoviridae↗

PubMed2003

Rheumatoid arthritis synovial fluid macrophages express decreased tumor necrosis factor-related apoptosis-inducing ligand R2 and increased decoy receptor tumor necrosis factor-related apoptosis-inducing ligand R3.

OBJECTIVE: To characterize the expression pattern of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its cognate receptors (TRAIL R1, R2, R3, and R4) on rheumatoid arthritis (RA) synovial fluid (SF) lymphocytes and monocyte/macrophages and on cultured RA synovial fibroblasts. METHODS: The expression of TRAIL and TRAIL receptors on RA SF lymphocytes and monocyte/macrophages, normal macrophages, and RA synovial fibroblasts was examined by flow cytometry with previously characterized monoclonal antibodies. The ability of adenoviral-mediated delivery of TRAIL to induce macrophage or RA synovial fibroblast apoptosis was examined by flow cytometry. RESULTS: By flow cytometry, neither TRAIL nor its cognate receptors was detectable on RA SF lymphocytes or RA synovial fibroblasts. In contrast, RA SF macrophages expressed TRAIL R3, a decoy receptor (P < 0.01 versus isotype control), but not TRAIL, or TRAIL R1, R2, or R4. Normal peripheral blood-derived monocyte-differentiated macrophages expressed TRAIL R2 (P < 0.01), but not TRAIL or the other TRAIL receptors. Adenoviral-mediated delivery of TRAIL had no effect on the survival of normal macrophages or RA synovial fibroblasts but readily induced apoptosis in the prostate cancer cell line (PC-3) that expressed TRAIL R1 and R2. CONCLUSION: TRAIL R1 and R2, which are required for signal transmission by TRAIL, were not detected on RA SF lymphocytes, macrophages, or synovial fibroblasts. These observations do not support a potential therapeutic role for TRAIL in RA.

Adenoviridae Infections↗

PubMed2003

CCN5 is a growth arrest-specific gene that regulates smooth muscle cell proliferation and motility.

Vascular smooth muscle cell (VSMC) hyperplasia plays an important role in both chronic and acute vascular pathologies. Considerable work has focused on the mechanisms regulating VSMC growth and the search for agents that could suppress VSMC hyperproliferation. One of the several inhibitors studied is the glycosaminoglycan heparin, which inhibits VSMC proliferation and migration both in cell culture and in animal models (Mishra-Gorur K, Delmolino LM, Castellot Jr JJ: Biological functions of heparan sulfate and heparan sulfate proteoglycans. Trends Glycosci Glycotechnol 1998, 10:193-210). To aid our understanding of the anti-proliferative mechanism of action of heparin, we used a subtractive hybridization approach to isolate and characterize a novel growth arrest-specific (gas) gene induced in VSMCs exposed to heparin (Delmolino LM, Stearns NA, Castellot Jr JJ: Heparin induces a member of the CCN family which has characteristics of a growth arrest specific gene. Mol Biol Cell 1997, 8:287a and Delmolino LM, Stearns NA, Castellot Jr JJ: COP-1, a member of the CCN family, is a heparin-induced growth arrest specific gene in vascular smooth muscle cells. J Cell Physiol 2001, 188:45-55). This gene is a member of the cysteine-rich 61/connective tissue growth factor/nephroblastoma-overexpressed (CCN) family and has been given the name CCN5. In this report, we provide functional evidence that CCN5 can inhibit VSMC proliferation, motility, and invasiveness. In contrast, adhesion and apoptosis are unaffected by CCN5 in this cell type. We also significantly extend previous data from our laboratory that suggests CCN5 is a growth arrest-specific (gas) gene. Furthermore, we map for the first time the cellular localization of CCN5 protein in cultured VSMCs. We also examine uninjured and balloon-injured rat carotid arteries for CCN5 expression. The results from the in vitro and in vivo localization studies show that CCN5 is temporally and spatially expressed in a manner consistent with a role in regulating proliferation, motility, and invasiveness of VSMCs.

Adenoviridae↗

PubMed2003

HMG-CoA reductase inhibitors promote cholesterol-dependent Akt/PKB translocation to membrane domains in endothelial cells.

OBJECTIVE: Recent results have shown that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors referred to as statins rapidly activate the protein kinase Akt/PKB in endothelial cells (ECs) and endothelial precursor cells (EPCs). This pathway is critical for cellular responses that contribute to angiogenesis and EC function including nitric oxide production, cellular survival and migration. METHODS: Here we tested whether statins control the translocation of recombinant and endogenous Akt to the plasma membrane of endothelial cells in a cholesterol-dependent manner. RESULTS: Low doses of statins rapidly induce the translocation of Akt to discrete sites in endothelial cell plasma membrane that colocalize with F-actin-positive, focal adhesion kinase (FAK)-negative lamellipodia and filopodia. This translocation event requires the lipid-binding, pleckstrin homology domain of Akt. Treatment with phosphoinositide 3-kinase (PI 3-kinase) inhibitors or the HMG-CoA reductase reaction product L-mevalonate blocks the translocation of Akt in response to statin stimulation. Furthermore, the ability of statins to promote Akt activation and translocation to the membrane is inhibited by cholesterol delivery to cells, but cholesterol loading had no effect on VEGF-induced Akt activation. CONCLUSIONS: These results suggest that statin activation of Akt signaling is mediated by the translocation of Akt to cholesterol-sensitive membrane structures within activated ECs.

Androstadienes↗

PubMed2003

Control of vascular cell differentiation by homeobox transcription factors.

Homeobox genes are a family of transcription factors with a highly conserved DNA-binding domain that regulate cell proliferation, differentiation, and migration in many cell types in diverse organisms. These properties are responsible for their critical roles in regulating pattern formation and organogenesis during embryogenesis. The cardiovascular system undergoes extensive remodeling during embryogenesis, and cardiovascular remodeling in the adult is associated with normal physiologic processes such as wound healing and the menstrual cycle, and disease states such as atherosclerosis, tumor-induced angiogenesis, and lymphedema. Aside from their roles in the formation of the embryonic vascular system, homeobox genes recently have been implicated in both physiologic and pathologic processes involving vascular remodeling in the adult, such as arterial restenosis after balloon angioplasty, physiologic and tumor-induced angiogenesis, and lymphangiogenesis. Understanding how homeobox genes regulate the phenotype of smooth muscle and endothelium in the vasculature will improve insight into the molecular mechanisms behind vascular cell differentiation and may suggest therapeutic interventions in human disease.

Animals↗

PubMed2003

Obesity, adiponectin and vascular inflammatory disease.

PURPOSE OF REVIEW: Obesity is the most common risk factor for cardiovascular diseases in industrial countries. It is now clear that adipose tissue secretes various bioactive substances, conceptualized as adipocytokines, and that dysregulation of adipocytokines directly contributes to obesity-related diseases. Chronic inflammatory processes contribute to the development of atherosclerosis. In this review, the authors focus on the relationship between adiponectin, a recently discovered anti-atherogenic adipocytokine, and vascular inflammation. RECENT FINDINGS: Plasma concentrations of adiponectin, an adipocyte-specific protein, are reduced in obese subjects and in patients with type 2 diabetes and coronary artery disease. Adiponectin inhibits the expression of tumor necrosis factor-alpha-induced endothelial adhesion molecules, macrophage-to-foam cell transformation, tumor necrosis factor-alpha expression in macrophages and adipose tissues, and smooth muscle cell proliferation. In addition, adenovirus-expressed adiponectin reduces atherosclerotic lesions in a mouse model of atherosclerosis, and adiponectin-deficient mice exhibit an excessive vascular remodeling response to injury. Clinically, hypoadiponectinemia is closely associated with increased levels of inflammatory markers such as C-reactive protein and interleukin-6. SUMMARY: Adiponectin acts as an anti-inflammatory and anti-atherogenic plasma protein. Adiponectin is an endogenous biologically relevant modulator of vascular remodeling linking obesity and vascular disease.

Adipocytes↗

PubMed2003

Statin therapy and angiogenesis.

PURPOSE OF REVIEW: Clinical studies suggested that 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy has an additional cardiovascular protective activity that may function independently of the ability of statins to lower serum cholesterol. This paper reviews the available data on these effects and discusses the potential intracellular mechanisms involved. RECENT FINDINGS: Experimental studies have clearly shown that statins protect against ischaemia-reperfusion injury of the heart, and exert pro-angiogenic effects by stimulating the growth of new blood vessels in ischaemic limbs of normocholesterolemic animals. The mechanisms underlying these serum lipid-independent statin effects are not completely understood, but there is increasing evidence that statins improve endothelial function through molecular mechanisms that mediate an increase in endothelium-derived nitric oxide. Recent research has revealed a link between statins and the serine/threonine protein kinase Akt that regulates multiple angiogenic processes in endothelial cells. In contrast to these data, it has also been reported that higher doses of statins can inhibit endothelial cell migration and angiogenesis. SUMMARY: Statins have biphasic potential either to promote or inhibit angiogenesis. Low statin doses induce a pro-angiogenic effect through Akt activation and increase nitric oxide production, whereas high statin doses may decrease protein prenylation and inhibit cell growth. Notwithstanding, the clinical relevance of these serum lipid-independent effects is not fully understood. Further studies on the actions of statins on endothelial cells may lead to the identification of new pharmacological targets for the control of angiogenesis.

Angiogenesis Modulating Agents↗

PubMed2002

Akt signaling mediates VEGF/VPF vascular permeability in vivo.

VEGF is an endothelial cell cytokine that promotes angiogenesis and enhances microvascular permeability. Recently, it has been shown that the protein kinase Akt functions in a key intercellular signaling pathway downstream of VEGF. Here, we employed adenovirus-mediated gene transfer in conjunction with the Miles assay in hairless albino guinea pigs to assess the role of Akt signaling in vascular permeability. VEGF-induced vascular permeability was blocked by the transduction of a dominant negative mutant of Akt. Conversely, transduction of a constitutively active form of Akt promoted vascular permeability in a manner similar to VEGF protein administration. This Akt-mediated increase in vascular permeability was inhibited by the eNOS inhibitor L-NAME. These data show that Akt signaling is both necessary and sufficient for vascular permeability in an in vivo model.

Animals↗

PubMed2002

Fas pathway is a critical mediator of cardiac myocyte death and MI during ischemia-reperfusion in vivo.

Fas is a widely expressed cell surface receptor that can initiate apoptosis when activated by its ligand (FasL). Whereas Fas abundance on cardiac myocytes increases in response to multiple pathological stimuli, direct evidence supporting its role in the pathogenesis of heart disease is lacking. Moreover, controversy exists even as to whether Fas activation induces apoptosis in cardiac myocytes. In this study, we show that adenoviral overexpression of FasL, but not beta-galactosidase, results in marked apoptosis both in cultures of primary neonatal cardiac myocytes and in the myocardium of intact adult rats. Myocyte killing by FasL is a specific event, because it does not occur in lpr (lymphoproliferative) mice that lack functional Fas. To assess the contribution of the Fas pathway to myocardial infarction (MI) in vivo, lpr mice were subjected to 30 min of ischemia followed by 24 h of reperfusion. Compared with wild-type mice, lpr mice exhibited infarcts that were 62.3% smaller with 63.8% less myocyte apoptosis. These data provide direct evidence that activation of Fas can induce apoptosis in cardiac myocytes and that Fas is a critical mediator of MI due to ischemia-reperfusion in vivo.

Animals↗

PubMed2002

Regulation of angiogenesis by glycogen synthase kinase-3beta.

Glycogen synthase kinase-3beta (GSK3beta) plays important roles in metabolism, embryonic development, and tumorigenesis. Here we investigated the role of GSK3beta signaling in vascular biology by examining its function in endothelial cells (ECs). In EC, the regulatory phosphorylation of GSK3beta was found to be under the control of phosphoinositide 3-kinase-, MAPK-, and protein kinase A-dependent signaling pathways. The transduction of a nonphosphorylatable constitutively active mutant of GSKbeta promoted apoptosis under the conditions of prolonged serum deprivation or the disruption of cell-matrix attachments. Conversely, the transduction of catalytically inactive GSK3beta promoted EC survival under the conditions of cellular stress. Under normal cell culture conditions, the activation of GSK3beta signaling inhibited the migration of EC to vascular endothelial growth factor or basic fibroblast growth factor. Angiogenesis was inhibited by GSK3beta activation in an in vivo Matrigel plug assay, whereas the inhibition of GSK3beta signaling enhanced capillary formation. These data suggest that GSK3beta functions at the nodal point of converging signaling pathways in EC to regulate vessel growth through its control of vascular cell migration and survival.

Anoikis↗

PubMed2002

Akt signaling mediates postnatal heart growth in response to insulin and nutritional status.

Akt is a serine-threonine kinase that mediates a variety of cellular responses to external stimuli. During postnatal development, Akt signaling in the heart was up-regulated when the heart was rapidly growing and was down-regulated by caloric restriction, suggesting a role of Akt in nutrient-dependent regulation of cardiac growth. Consistent with this notion, reductions in Akt, 70-kDa S6 kinase 1, and eukaryotic initiation factor 4E-binding protein 1 phosphorylation were observed in mice with cardiac-specific deletion of insulin receptor gene, which exhibit a small heart phenotype. In contrast to wild type animals, caloric restriction in these mice had little effect on Akt phosphorylation in the heart. Furthermore, forced expression of Akt1 in these hearts restored 70-kDa S6 kinase 1 and eukaryotic initiation factor 4E-binding protein 1 phosphorylation to normal levels and rescued the small heart phenotype. Collectively, these results indicate that Akt signaling mediates insulin-dependent physiological heart growth during postnatal development and suggest a mechanism by which heart size is coordinated with overall body size as the nutritional status of the organism is varied.

Aging↗

PubMed2002

Mouse genetic evidence that tranilast reduces smooth muscle cell hyperplasia via a p21(WAF1)-dependent pathway.

OBJECTIVE: N-(3'4'-dimethoxycinnamoyl)-anthranilic acid (tranilast) is a drug that has been shown to reduce the incidence of restenosis after angioplasty in middle-scale clinical trials. Despite clinical interest in this drug, the pharmacological actions of tranilast remain relatively unexplored at a molecular level. METHODS AND RESULTS: We evaluated the effects of tranilast on vascular smooth muscle cell (VSMC) proliferation in wild-type mice and in mice lacking a cyclin-dependent kinase inhibitor, p21(WAF1) (p21). Tranilast potently inhibited the proliferation of VSMC cultures derived from wild-type mice, but VSMCs derived from p21-deficient (p21-/-) mice were unaffected by this treatment. In a mouse femoral artery model of vascular injury, tranilast administration to wild-type mice led to an upregulation of p21 expression and a decrease in the number of proliferating VSMCs, as determined by immunostaining for proliferating cell nuclear antigen. In contrast, tranilast had no effect on the number of proliferating cell nuclear antigen-positive cells in the injured arteries of p21-/- mice. Administration of tranilast significantly reduced the neointimal VSMC hyperplasia in wild-type mice at 4 weeks but had no effect on lesion formation in p21-/- mice. CONCLUSIONS: Our findings provide genetic evidence that tranilast inhibits intimal hyperplasia via a p21-dependent pathway, an activity that may contribute to its efficacy in the prophylactic treatment of postangioplasty restenosis.

Animals↗

PubMed2002

Modulation by peroxynitrite of Akt- and AMP-activated kinase-dependent Ser1179 phosphorylation of endothelial nitric oxide synthase.

Peroxynitrite (ONOO(-)), a nitric oxide-derived oxidant, uncouples endothelial nitric oxide synthase (eNOS) and increases enzymatic production of superoxide anions (O(2)()) (Zou, M. H., Shi, C., and Cohen, R. A. (2002) J. Clin. Invest. 109, 817-826). Here we studied how ONOO(-) influences eNOS activity. In cultured bovine aortic endothelial cells (BAEC), ONOO(-) increased basal and agonist-stimulated Ser(1179) phosphorylation of eNOS, whereas it decreased nitric oxide production and bioactivity. However, ONOO(-) strongly inhibited the phosphorylation and activity of Akt, which is known to phosphorylate eNOS-Ser(1179). Moreover, expression of an Akt dominant-negative mutant did not prevent ONOO(-)-enhanced eNOS-Ser(1179) phosphorylation. In contrast to Akt, ONOO(-) significantly activated 5'-AMP-activated kinase (AMPK), as evidenced by its increased Thr(172) phosphorylation as well as increased Ser(92) phosphorylation of acetyl-coenzyme A carboxylase, a downstream target of AMPK. Associated with the increased release of O(2)(), ONOO(-) significantly increased the co-immunoprecipitation of eNOS with AMPK. Further, overexpression of the AMPK-constitutive active adenovirus significantly enhanced ONOO(-) up-regulated eNOS-Ser(P)(1179). In contrast, overexpression of a dominant-negative AMPK mutant attenuated the ONOO(-)-enhanced eNOS-Ser(1179) phosphorylation as well as O(2)() release. We conclude that ONOO(-) inhibits Akt and increases AMPK-dependent Ser(1179) phosphorylation of eNOS resulting in enhanced O(2)() release.

AMP-Activated Protein Kinases↗

PubMed2002

Role of Akt signaling in vascular homeostasis and angiogenesis.

Akt is a serine/threonine protein kinase that is activated by a number of growth factors and cytokines in a phosphatidylinositol-3 kinase-dependent manner. Although antiapoptotic activity of Akt is well known, it also regulates other aspects of cellular functions, including migration, glucose metabolism, and protein synthesis. In this review, Akt signaling in endothelial cells and its critical roles in the regulation of vascular homeostasis and angiogenesis will be discussed.

Animals↗

PubMed2002

Angiotensin II induces myocyte enhancer factor 2- and calcineurin/nuclear factor of activated T cell-dependent transcriptional activation in vascular myocytes.

It is well known that angiotensin II (Ang II) is implicated in the phenotypic modulation and hypertrophy of vascular smooth muscle cells (VSMCs). To study the mechanisms by which Ang II contributes to the pathological changes of VSMCs, we examined whether Ang II stimulated myocyte enhancer factor 2 (MEF2)- and calcineurin/nuclear factor of activated T cell (NFAT)-dependent transcriptional activation of genes in VSMCs. Ang II increased the DNA binding activity of MEF2A and its expression at the protein level. Ang II induced c-jun promoter activity, and this increase was inhibited by dominant-negative mutants of MEF2A and mitogen-activated protein kinase kinase 6 but not by calcineurin inhibitors. Ang II stimulated NFAT DNA binding activity and NFAT-dependent gene transcription, and these effects of Ang II were inhibited by calcineurin inhibitors. Furthermore, Ang II induced the promoter activity of the nonmuscle-type myosin heavy chain B gene, which we used as a marker of the dedifferentiated state of VSMCs, and this increase was inhibited by calcineurin inhibitors but not by the dominant-negative mutants of MEF2A or mitogen-activated protein kinase kinase 6. Finally, Ang II increased protein synthesis, and this increase was inhibited by infection with an adenovirus construct that expresses the dominant-negative mutant of MEF2A but not by calcineurin inhibitors. These results suggest that Ang II stimulates the MEF2- and calcineurin/NFAT-dependent pathways and that these pathways have distinct roles in VSMCs.

Angiotensin II↗

PubMed2002

Spatial and temporal control of transgene expression through ultrasound-mediated induction of the heat shock protein 70B promoter in vivo.

Adenoviral vectors have been constructed that express the transgenes luciferase (Adeno-HSP-Luc) or Fas ligand (Adeno-HSP-FasL) under the control of the heat shock protein 70B (hsp70B) promoter. Cultures infected with Adeno-HSP-Luc transiently expressed high levels of luciferase after heat shock. When cultures infected with Adeno-HSP-FasL were maintained at 37 degrees C, no transgene expression was observed, but when cultures were exposed to heat stress, transgene expression resulted in apoptotic cell death. In vivo, transgene expression was induced by ultrasound-mediated heating of adenovirus-infected tissue. In mice or rats injected with the Adeno-HSP-Luc construct, high levels of localized expression of luciferase activity were observed in regions subjected to ultrasound-mediated irradiation. Adeno-HSP-FasL was administered systemically to mice via the tail vein to evaluate safety. Animals receiving Adeno-HSP-FasL in the absence of ultrasound treatment did not display liver toxicity, whereas animals receiving ultrasound treatment to induce the expression of Fas ligand from the hsp70B promoter had significant increases in serum levels of liver enzymes. These data demonstrate that combining the inducible hsp70B promoter with ultrasound induction allows safe local expression of cytotoxic genes with possible therapeutic utility.

Adenoviruses, Human↗

PubMed2002

Elevated myocardial Akt signaling ameliorates doxorubicin-induced congestive heart failure and promotes heart growth.

Doxorubicin is a chemotherapeutic agent that can induce cardiotoxicity and congestive heart failure (CHF). In this study we tested whether intracoronary Akt1 gene delivery could inhibit doxorubicin-induced CHF. Saline or a replication defective adenoviral vector expressing constitutively-active Akt1 (myrAkt) or beta-galactosidase (betagal) was delivered to the myocardium of 8 week old rats one day prior to initiating doxorubicin administration. In animals receiving saline or betagal, doxorubicin resulted in significant decreases in cardiac function and retarded post-natal heart growth at the 5 weeks time point. In contrast, transduction of myrAkt protected hearts against doxorubicin-induced decreases in fractional shortening and cardiac index, and improved left ventricular function at 5 weeks time point. Delivery of myrAkt also reversed the doxorubicin-induced reduction in post-natal heart growth and diminished lung edema. These data show that myocardial Akt can inhibit doxorubicin-induced reductions in cardiac function and growth, suggesting that manipulation of this signaling pathway may have utility for the treatment of congestive heart failure.

Animals↗