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R T Lee

Publications and source records attributed to R T Lee.

At least 19 recordsLinked to original sources
PubMed2001

Peroxisome proliferator-activated receptor gamma activators inhibit cardiac hypertrophy in cardiac myocytes.

BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. PPARgamma mRNA is present in cardiac myocytes; however, whether PPARgamma affects cardiac hypertrophy remains unknown. METHODS AND RESULTS: We investigated the effects of PPARgamma activators on cardiac hypertrophy in neonatal rat cardiac myocytes. Cyclic 4% biaxial mechanical strain caused enlargement of cardiac myocytes (1.3-fold versus control, P<0.0001), but the PPARgamma activators troglitazone and 15-deoxy-Delta(12-14)-prostaglandin J(2) (15d-PGJ(2)) (10 micromol/L) inhibited this effect (troglitazone, -72%, P<0.0005; 15d-PGJ(2), -88%, P<0.0002). Total cell protein was increased by mechanical strain (control, 164.3 microgram/dish; strain, 265.5, P<0.0002), and this effect was inhibited by troglitazone and 15d-PGJ(2) (troglitazone, -61%, P<0.005; 15d-PGJ(2), -72%, P<0.001). [(3)H]Leucine uptake was also increased by mechanical strain (1.9-fold versus control, P<0.002), and this increase was inhibited by troglitazone and 15d-PGJ(2) (troglitazone, -52% at 10 micromol/L, P<0.01; 15d-PGJ(2), -70% at 10 micromol/L, P<0.005). An increase in [(3)H]leucine uptake induced by angiotensin II or phenylephrine was significantly inhibited by troglitazone and 15d-PGJ(2). Mechanical strain induced mRNA expression for brain natriuretic peptide, but PPARgamma activators inhibited this induction. Furthermore, PPARgamma activators inhibited mechanically induced activation of nuclear factor (NF)-kappaB. Pyrrolidine dithiocarbamate, an inhibitor of NF-kappaB activation, inhibited strain-induced [(3)H]leucine uptake (-50% at 100 micromol/L, P<0.05). CONCLUSIONS: These results demonstrate that PPARgamma activators inhibit cardiac hypertrophy in cardiac myocytes and suggest that PPARgamma activators may regulate cardiomyocyte hypertrophy at least partially through the NF-kappaB pathway.

Angiotensin II↗
PubMed2001

Endothelial nitric oxide synthase limits left ventricular remodeling after myocardial infarction in mice.

Background- To investigate the role of endothelial nitric oxide synthase (NOS3) in left ventricular (LV) remodeling after myocardial infarction (MI), the impact of left anterior descending coronary artery ligation on LV size and function was compared in 2- to 4-month-old wild-type (WT) and NOS3-deficient mice (NOS3(-/-)). Methods and Results- Two days after MI, both strains of mice had a similar LV size, fractional shortening, and ejection fraction by echocardiography. Twenty-eight days after MI, both strains had dilated LVs with decreased fractional shortening and lower ejection fractions. Although the infarcted fraction of the LV was similar in both strains, LV end-diastolic internal diameter, end-diastolic volume, and mass were greater, but fractional shortening, ejection fraction, and the maximum rate of developed LV pressure (dP/dt(max)) were lower in NOS3(-/-) than in WT mice. Impairment of diastolic function, as measured by the time constant of isovolumic relaxation (tau) and the maximum rate of LV pressure decay (dP/dt(min)), was more marked in NOS3(-/-) than in WT mice. Mortality after MI was greater in NOS3(-/-) than in WT mice. Long-term administration of hydralazine normalized blood pressure in NOS3(-/-) mice, but it did not prevent the LV dilatation, impaired systolic and diastolic function, and increased LV mass that followed MI. In WT mice, capillary density and myocyte width in the nonischemic portion of the LV did not differ before and 28 days after MI, whereas in NOS3(-/-) mice, capillary density decreased and myocyte width increased after MI, whether or not hydralazine was administered. Conclusions- These results suggest that the presence of NOS3 limits LV dysfunction and remodeling in a murine model of MI by an afterload-independent mechanism, in part by decreasing myocyte hypertrophy in the remote myocardium.

Animals↗
PubMed2001

An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/- mice.

PTEN phosphatase acts as a tumor suppressor by negatively regulating the phosphoinositide 3-kinase (PI3K) signaling pathway. It is unclear which downstream components of this pathway are necessary for oncogenic transformation. In this report we show that transformed cells of PTEN(+/-) mice have elevated levels of phosphorylated Akt and activated p70/S6 kinase associated with an increase in proliferation. Pharmacological inactivation of mTOR/RAFT/FRAP reduced neoplastic proliferation, tumor size, and p70/S6 kinase activity, but did not affect the status of Akt. These data suggest that p70/S6K and possibly other targets of mTOR contribute significantly to tumor development and that inhibition of these proteins may be therapeutic for cancer patients with deranged PI3K signaling.

Alleles↗
PubMed2001

Biomechanical strain induces class a scavenger receptor expression in human monocyte/macrophages and THP-1 cells: a potential mechanism of increased atherosclerosis in hypertension.

BACKGROUND: Although hypertension is an important risk factor for the development of atherosclerosis, the mechanisms for this interaction are incompletely described. Previous studies have suggested that biomechanical strain regulates macrophage phenotype. We tested the hypothesis that biomechanical strain can induce expression of the class A scavenger receptor (SRA), an important lipoprotein receptor in atherogenesis. METHODS AND RESULTS: Human monocyte/macrophages or THP-1 cells were cultured in a device that imposes uniform biaxial cyclic 1-Hz strains of 0%, 1%, 2%, or 3%, and SRA expression was analyzed. Mechanical strains induced SRA mRNA (3.5+/-0.6-fold at 3% strain for 48 hours, P<0.01) and SRA protein in THP-1 cells in an amplitude-dependent manner. This induction was accompanied by augmented expression of the class B scavenger receptor CD36 (2.8+/-0.3-fold, P<0.001) but not by increased peroxisome proliferator-activated receptor-gamma expression. To evaluate this effect in vivo, apolipoprotein E(-/-) mice were randomly assigned to receive standard chow, a high-cholesterol diet, or a high-cholesterol diet with hypertension induced by angiotensin II infusion for 8 weeks. Immunohistochemistry revealed that among macrophages in atherosclerotic lesions of the aorta, the proportion of macrophages with SRA expression was highest in hypertensive animals on a high-cholesterol diet (43.9+/-0.7%, versus 12.0+/-2.0% for normotensive animals on a high-cholesterol diet and 4.7+/-4.7% for animals on standard chow; P<0.001). CONCLUSIONS: Biomechanical strain induces SRA expression by monocyte/macrophages, suggesting a novel mechanism for promotion of atherosclerosis in hypertensive patients.

Angiotensin II↗
PubMed2001

Regulation of cardiomyocyte mechanotransduction by the cardiac cycle.

BACKGROUND: Overloading the left ventricle in systole (pressure overload) is associated with a distinct morphological response compared with overload in diastole (volume overload). METHODS AND RESULTS: We designed a novel computer-controlled experimental system that interfaces biaxially uniform strain with electrical pacing, so that cellular deformation can be imposed during a specified phase of the cardiac cycle. Cardiomyocytes were exposed to strain (4%) during either the first third (systolic phase) or last third (diastolic phase) of the cardiac cycle. Strain imposed during the systolic phase selectively activated p44/42 mitogen-activated protein kinase (MAPK) and MAPK/extracellular signal-regulated protein kinase kinase (MEK1/2, an activator of p44/42 MAPK) compared with strain imposed during the diastolic phase. In contrast, there was no difference in activation of p38 and c-Jun NH(2)-terminal kinases induced by strain imposed during the systolic phase (5.8- and 3.3-fold versus control, n=4) compared with the diastolic phase (5.5- and 3.1-fold). Induction of both brain natriuretic peptide (5.8-fold versus control, P:<0.05, n=3) and tenascin-C (7.0-fold, P:<0.02) mRNA expression by strain imposed during the systolic phase was greater than during the diastolic phase (3.9- and 3.6-fold, respectively). [(3)H]leucine incorporation induced by strain imposed during the systolic phase (4.0-fold versus control) was greater than during the diastolic phase (2.7-fold, P:<0.02, n=4); a selective inhibitor of MEK1/2 inhibited this difference. CONCLUSIONS: Mechanical activation of p44/42 MAPK and MEK1/2, gene expression, and protein synthesis is regulated by the cardiac cycle, suggesting that mechanotransduction at the cellular level may underlie differences between pressure and volume overload of the heart.

Animals↗
PubMed2001

Usefulness of transthoracic echocardiography as a tool for risk stratification of patients undergoing major noncardiac surgery.

Transthoracic echocardiography (TTE) is frequently ordered before noncardiac surgery, although its ability to predict perioperative cardiac complications is uncertain. To evaluate the incremental information provided by TTE after consideration of clinical data for prediction of cardiac complications after noncardiac surgery, 570 patients who underwent TTE before major noncardiac surgery at a university hospital were studied. Preoperative clinical data and clinical outcomes were collected prospectively according to a structured protocol. TTE data included left ventricular (LV) function, hypertrophy indexes, and Doppler-derived measurements. In univariate analyses, preoperative systolic dysfunction was associated with postoperative myocardial infarction (odds ratio [OR] 2.8, 95% confidence interval [CI] 1.1 to 7.0), cardiogenic pulmonary edema (OR 3.2, 95% CI 1.4 to 7.0), and major cardiac complications (OR 2.4, 95% Cl 1.3 to 4.5). Moderate to severe LV hypertrophy, moderate to severe mitral regurgitation, and increased aortic valve gradient were also associated with major cardiac events (OR 2.3, 95% CI 1.2 to 4.6; OR 2.2, 95% CI 1.1 to 4.3; OR 2.1, 95% CI 1.0 to 4.5, respectively). In logistic regression analysis, models with echocardiographic variables predicted major cardiac complications significantly better than those that included only clinical variables (c statistic 0.73 vs 0.68; p <0.05). Echocardiographic data added significant information for patients at increased risk for cardiac complications by clinical criteria, but not in otherwise low-risk patients. In conclusion, preoperative TTE before noncardiac surgery can provide independent information about the risk of postoperative cardiac complications in selected patients.

Aged↗
PubMed2001

The impact of calcification on the biomechanical stability of atherosclerotic plaques.

BACKGROUND: Increased biomechanical stresses in the fibrous cap of atherosclerotic plaques contribute to plaque rupture and, consequently, to thrombosis and myocardial infarction. Thin fibrous caps and large lipid pools are important determinants of increased plaque stresses. Although coronary calcification is associated with worse cardiovascular prognosis, the relationship between atheroma calcification and stresses is incompletely described. METHODS AND RESULTS: To test the hypothesis that calcification impacts biomechanical stresses in human atherosclerotic lesions, we studied 20 human coronary lesions with techniques that have previously been shown to predict plaque rupture locations accurately. Ten ruptured and 10 stable lesions derived from post mortem coronary arteries were studied using large-strain finite element analysis. Maximum stress was not correlated with percentage of calcification, but it was positively correlated with the percentage of lipid (P:=0.024). When calcification was eliminated and replaced with fibrous plaque, stress changed insignificantly; the median increase in stress for all specimens was 0.1% (range, 0% to 8%; P:=0.85). In contrast, stress decreased by a median of 26% (range, 1% to 78%; P:=0.02) when lipid was replaced with fibrous plaque. CONCLUSIONS: Calcification does not increase fibrous cap stress in typical ruptured or stable human coronary atherosclerotic lesions. In contrast to lipid pools, which dramatically increase stresses, calcification does not seem to decrease the mechanical stability of the coronary atheroma.

Adult↗
PubMed2001

Mechanical strain induces specific changes in the synthesis and organization of proteoglycans by vascular smooth muscle cells.

In the mechanically active environment of the artery, cells sense mechanical stimuli and regulate extracellular matrix structure. In this study, we explored the changes in synthesis of proteoglycans by vascular smooth muscle cells in response to precisely controlled mechanical strains. Strain increased mRNA for versican (3.2-fold), biglycan (2.0-fold), and perlecan (2.0-fold), whereas decorin mRNA levels decreased to a third of control levels. Strain also increased versican, biglycan, and perlecan core proteins, with a concomitant decrease in decorin core protein. Deformation did not alter the hydrodynamic size of proteoglycans as evidenced by molecular sieve chromatography but increased sulfate incorporation in both chondroitin/dermatan sulfate proteoglycans and heparan sulfate proteoglycans (p < 0.05 for both). Using DNA microarrays, we also identified the gene for the hyaluronan-linking protein TSG6 as mechanically induced in smooth muscle cells. Northern analysis confirmed a 4.0-fold increase in steady state mRNA for TSG6 following deformation. Size exclusion chromatography under associative conditions showed that versican-hyaluronan aggregation was enhanced following deformation. These data demonstrate that mechanical deformation increases specific vascular smooth muscle cell proteoglycan synthesis and aggregation, indicating a highly coordinated extracellular matrix response to biomechanical stimulation.

Aorta↗
PubMed2001

Specific association of 36Cl with low molecular weight humic substances in soils.

Soils initially contaminated with 36Cl in the chloride form were subjected to solid-liquid extractions using a variety of reagents including deionised water and 1 M sodium hydroxide (NaOH). 1 M NaOH was found to result in the greatest recovery of 36Cl from the soils, a result which provided initial evidence that radioactive chlorine became attached to humic substances present naturally within the soils. Deionised water and 1 M NaOH extracts were subjected to analysis involving separation by gel filtration chromatography (GFC). It was found that 36Cl in 1 M NaOH extracts associated preferentially with low molecular weight (LMW) fractions of humic substances whereas, in deionised water extracts, 36Cl appeared to be present exclusively in the chloride form. Previous literature evidence, mainly from highly organic forest soils, suggests that conversion of stable chlorine from chloride to organic forms can occur as a result of biological action. The present paper also presents good evidence for the specific attachment of stable chlorine (37Cl) to a LMW humic fraction, again demonstrated using GFC separation. Current risk assessments of the deep geological disposal of solid radioactive wastes containing 36Cl typically assume a very low degree of sorption based on the notion that the predominant environmental species of radiochlorine is chloride. This paper concludes with a brief discussion on the implications of organochlorine formation in the biosphere for assessment of the radiological impact of deep geological disposal of solid radioactive wastes.

Adsorption↗
PubMed2001

Matrix metalloproteinase inhibition and the prevention of heart failure.

Matrix metalloproteinases (MMPs) are members of a large family of enzymes that can degrade extracellular matrix as well as other molecules. MMPs participate in a broad variety of normal and pathologic states, and recent evidence implicates the MMP family as potential mediators of cardiac dilation and progression to heart failure. This evidence is based on several lines of investigation. First, members of the MMP family are overexpressed in the myocardium in both experimental and human myocardial injury, infarction, and dilation. Second, overexpression of at least one MMP (MMP-1) in the hearts of transgenic mice can cause cardiac hypertrophy, dilation, and systolic dysfunction. Third, studies from multiple laboratories with different experimental models indicate that inhibition of MMPs through small molecules or gene transfer of endogenous inhibitors favorably affects cardiac remodeling. Fourth, targeted deletion of MMP genes in mice attenuates cardiac remodeling. These compelling results appear to fulfill Koch's Postulates as they may be applied to a non-infectious mediator of a disease, and thus current evidence supports MMP inhibition as a promising strategy for preventing heart failure. However, the crucial question of whether MMP inhibition benefits long-term left ventricular function and survival should be answered.

Animals↗
PubMed2001

Regional wall stress predicts ventricular remodeling after anteroseptal myocardial infarction in the Healing and Early Afterload Reducing Trial (HEART): an echocardiography-based structural analysis.

BACKGROUND: Increased left ventricular (LV) wall stress after myocardial infarction (MI) has been implicated in LV remodeling. However, the relationship between LV wall stress and LV remodeling is incompletely defined. METHOD: We prospectively studied the relationship between regional wall stress and LV remodeling by application of the finite element method to end-systolic LV models from patients enrolled in the Healing and Early Afterload Reducing Therapy (HEART) Trial. Individual LV models were constructed from orthogonal apical echocardiographic views obtained at day 14 after anteroseptal MI in 64 patients. Of these, 31 patients received low-dose (0.625 mg) ramipril and 33 patients received full-dose (10 mg) ramipril. LV wall stress was calculated by the finite element method and correlated with change in LV volume from day 14 to day 90 after MI. RESULTS: Among all patients, increases in apical regional wall stress were associated with LV volume changes (P -trend =.015). The relationship between apical regional wall stress and change in LV volume was strongest in the low-dose ramipril group (r = 0.53, P =.002) and remained significant after adjustment for end-diastolic volume, infarct size, ejection fraction, and systolic blood pressure yet was attenuated in the full-dose ramipril group. CONCLUSIONS: Apical regional wall stress is an independent predictor of subsequent LV remodeling after MI. The relationship between increased apical wall stress and LV dilatation appears to be attenuated by full-dose angiotensin-converting enzyme inhibition.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

A prospective optical surface scanning and cephalometric assessment of the effect of functional appliances on the soft tissues.

The aim of this study was to evaluate the effect of different functional appliances on the soft tissues as assessed by cephalometry and optical surface scanning. Forty-two patients were randomly allocated to Bass, Twin Block (TB), and Twin Block + Headgear (TB + Hg) groups. Lateral cephalograms and optical surface scans were recorded before and after the 10-month study period. ANOVA was used to test the cephalometric variables for differences at the 5 per cent level. The optical surface scanning and cephalometric results were consistent in the sagittal dimension. In the vertical dimension, however, the optical surface scans consistently recorded a greater increase compared with cephalometric values. No differences were detected with regard to cephalometric values at the 5 per cent level. However, the Bass appliance produced greater forward positioning of soft tissue pogonion as assessed by optical surface scanning.

Analysis of Variance↗
PubMed2001

Blood pressure and inflammation in apparently healthy men.

Inflammation plays an important role in the development of atherosclerosis, but the specific stimuli governing cytokine release in atherogenesis are unknown. We examined the hypothesis that hypertension may increase the risk of atherosclerosis via proinflammatory effects. In a cross-sectional study involving 508 apparently healthy men, we studied the association between blood pressure and baseline plasma concentrations of 2 inflammatory markers, intercellular adhesion molecule-1 (sICAM-1) and interleukin-6 (IL-6). Increase in systolic blood pressure (SBP) (P=0.003), pulse pressure (PP) (P=0.019), and mean arterial pressure (P=0.014) was significantly associated with levels of sICAM-1. All of these measures of blood pressure, as well as diastolic blood pressure (DBP), were significantly associated with levels of IL-6 (all, P</=0.001). In multiple linear regression models controlled for age and other cardiac risk factors, SBP (7.6 ng/mL per 10 mm Hg, P=0.016) and PP (8.13 ng/mL per 10 mm Hg, P=0.038) were significantly associated with sICAM-1 levels, whereas SBP (0.11 pg/mL per 10 mm Hg, P<0.001), DBP (0.11 pg/mL per 10 mm Hg, P=0.008), PP (0.10 pg/mL per 10 mm Hg, P=0.009), and mean arterial pressure (0.15 pg/mL per 10 mm Hg, P<0.001) had similar strong relationships with log-transformed IL-6 levels. Therefore, in apparently healthy men, we observed significant graded relationships between blood pressure and levels of sICAM-1 as well as IL-6. These data suggest that increased blood pressure may be a stimulus for inflammation and that this is a possible mechanism underlying the well-established role of hypertension as a risk factor for atherosclerotic disease.

Blood Pressure↗
PubMed2000

Overexpression of eotaxin and the CCR3 receptor in human atherosclerosis: using genomic technology to identify a potential novel pathway of vascular inflammation.

BACKGROUND: Unstable atherosclerotic lesions typically have an abundant inflammatory cell infiltrate, including activated T cells, macrophages, and mast cells, which may decrease plaque stability. The pathophysiology of inflammatory cell recruitment and activation in the human atheroma is incompletely described. METHODS AND RESULTS: We hypothesized that differential gene expression with DNA microarray technology would identify new genes that may participate in vascular inflammation. RNA isolated from cultured human aortic smooth muscle cells treated with tumor necrosis factor-alpha (TNF-alpha) was examined with a DNA microarray with 8600 genes. This experiment and subsequent Northern analyses demonstrated marked increases in steady-state eotaxin mRNA (>20 fold), a chemokine initially described as a chemotactic factor for eosinophils. Because eosinophils are rarely present in human atherosclerosis, we then studied tissue samples from 7 normal and 14 atherosclerotic arteries. Immunohistochemical analysis demonstrated overexpression of eotaxin protein and its receptor, CCR3, in the human atheroma, with negligible expression in normal vessels. Eotaxin was predominantly located in smooth muscle cells. The CCR3 receptor was localized primarily to macrophage-rich regions as defined by immunopositivity for CD 68; a minority of mast cells also demonstrated immunopositivity for the CCR3 receptor. CONCLUSIONS: Eotaxin and its receptor, CCR3, are overexpressed in human atherosclerosis, suggesting that eotaxin participates in vascular inflammation. These data demonstrate how genomic differential expression technology can identify novel genes that may participate in the stability of atherosclerotic lesions.

Actins↗
PubMed2000

Matrix matters.

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Animals↗
PubMed2000

Plaque stabilization: the role of lipid lowering.

The unstable atheroma characteristically has a thin, eccentric fibrous cap and a large necrotic core of lipid and cellular debris. This plaque configuration is particularly unstable because large mechanical stresses develop in the thinnest portions of the fibrosis cap over the lipid pool. Numerous recent observations tell us that critical biological factors other than lesion morphology also contribute to the ultimate fracture of the fibrous cap. Matrix-degrading enzymes, particularly members of the metalloproteinase family, are overexpressed in atherosclerotic tissue. The regions with the greatest amounts of these enzymes are the critical high stress regions, which are usually also infiltrated with inflammatory cells. At the cellular level a number of factors regulate expression of these enzymes by vascular smooth muscle cells. These factors include mechanical stimuli and cytokines known to be overexpressed in atheroma by both smooth muscle cells and macrophages. Low density lipoprotein cholesterol in the lesion plays a significant role in most or all of these processes, and our current understanding of the unstable atheroma is consistent with the dramatic clinical successes of lipid-lowering therapy.

Animals↗
PubMed2000

Direct extracellular contact between integrin alpha(3)beta(1) and TM4SF protein CD151.

Previously we established that the alpha(3)beta(1) integrin shows stable, specific, and stoichiometric association with the TM4SF (tetraspannin) protein CD151. Here we used a membrane impermeable cross-linking agent to show a direct association between extracellular domains of alpha(3)beta(1) and CD151. The alpha(3)beta(1)-CD151 association site was then mapped using chimeric alpha(6)/alpha(3) integrins and CD151/NAG2 TM4SF proteins. Complex formation required an extracellular alpha(3) site (amino acids (aa) 570-705) not previously known to be involved in specific integrin contacts with other proteins and a region (aa 186-217) within the large extracellular loop of CD151. Notably, the anti-CD151 monoclonal antibody TS151r binding epitope, previously implicated in alpha(3) integrin association, was mapped to the same region of CD151 (aa 186-217). Finally, we demonstrated that both NH(2)- and COOH-terminal domains of CD151 are located on the inside of the plasma membrane, thus confirming a long suspected model of TM4SF protein topology.

Amino Acid Sequence↗