Biomedical subjects

Richard H Karas

Publications and source records attributed to Richard H Karas.

At least 19 recordsLinked to original sources

PubMed2006

RACK1 is a BKCa channel binding protein.

The large conductance calcium-activated potassium channel, or BK(Ca) channel, plays an important feedback role in a variety of physiological processes, including neurotransmitter release and smooth muscle contraction. Some reports have suggested that this channel forms a stable complex with regulators of its function, including several kinases and phosphatases. To further define such signaling complexes, we used the yeast two-hybrid system to screen a human aorta cDNA library for proteins that bind to the BK(Ca) channel's intracellular, COOH-terminal "tail". One of the interactors we identified is the protein receptor for activated C kinase 1 (RACK1). RACK1 is a member of the WD40 protein family, which also includes the G protein beta-subunits. Consistent with an important role in BK(Ca)-channel regulation, RACK1 has been shown to be a scaffolding protein that interacts with a wide variety of signaling molecules, including cSRC and PKC. We have confirmed the interaction between RACK1 and the BK(Ca) channel biochemically with GST pull-down and coimmunoprecipitation experiments. We have observed some co-localization of RACK1 with the BK(Ca) channel in vascular smooth muscle cells with immunocytochemical experiments, and we have found that RACK1 has effects on the BK(Ca) channel's biophysical properties. Thus RACK1 binds to the BK(Ca) channel and it may form part of a BK(Ca)-channel regulatory complex in vascular smooth muscle.

Amino Acid Sequence↗

PubMed2006

Extent to which accepted serum lipid goals are achieved in a contemporary general medical population with coronary heart disease risk equivalents.

This study examined lipid levels and the use of lipid-altering drugs in a contemporary general medical population without documented coronary heart disease (CHD) but with CHD risk equivalents. On the basis of present national guidelines, the following lipid values (in milligrams per deciliter) were considered optimal for this population: low-density lipoprotein cholesterol <100, high-density lipoprotein (HDL) cholesterol >or=40 in men and >or=50 in women, and non-HDL cholesterol <130 if triglycerides are >or=200. Of 44,052 active patients screened, 877 with CHD risk equivalents as defined by the Adult Treatment Panel III guidelines were identified. Most patients did not meet optimal lipid targets for low-density lipoprotein cholesterol (59%), HDL cholesterol (66%), and non-HDL cholesterol (72%). Indeed, 88% of patients did not meet >or=1 lipid goal. Statins were used in 57% of patients. In patients with low HDL cholesterol, only 4.7% were taking niacin and 4.9% fibrates. In the subgroup of patients with triglycerides >or=200 mg/dl, only 9.5% were taking fibrates and 8.2% niacin. In conclusion, the present analysis highlights the dramatic need to further improve preventive measures in a substantial proportion of high-risk patients with CHD risk equivalents.

Aged↗

PubMed2006

Effects of extended-release niacin on lipoprotein particle size, distribution, and inflammatory markers in patients with coronary artery disease.

In this study, niacin was added to existing therapy for 3 months in 54 subjects with stable coronary artery disease. Average total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride levels were similar between groups. Three months of niacin treatment increased total HDL by 7.5% and decreased triglycerides by 15% compared with baseline values (p <0.005 for each), whereas total cholesterol and LDL levels remained unchanged. Addition of niacin resulted in a 32% increase in large-particle HDL (p <0.001), an 8% decrease in small-particle HDL (p = 0.0032), an 82% increase in large-particle LDL (p = 0.09), and a 12% decrease in small-particle LDL (p = 0.008). Niacin decreased lipoprotein-associated phospholipase A2 and C-reactive protein levels (20% and 15%, respectively, p <0.05 for the 2 comparisons). No significant changes from baseline were seen in any tested parameter in subjects who received placebo. In conclusion, addition of niacin to existing medical regimens for patients with coronary artery disease and already well-controlled LDL levels favorably improves the distribution of lipoprotein particle sizes and inflammatory markers in a manner that would be expected to confer atheroprotection. The effect of altering lipoprotein particle distribution and inflammatory markers on surrogate markers of atherosclerosis and clinical cardiovascular events in this population remains unclear.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed2006

Hormone replacement therapy and the cardiovascular system lessons learned and unanswered questions.

Cardiovascular disease is the leading cause of death among women in the U.S., exceeding breast cancer mortality in women of all ages. Women present with cardiovascular disease a decade after men, and this has been attributed to the protective effect of female ovarian sex hormones that is lost after menopause. Animal and observational studies have shown beneficial effects of hormone therapy when it is initiated early in the perimenopausal period or before the development of significant atherosclerosis. However, randomized, placebo-controlled trials in older women have not shown any benefit in either primary prevention or secondary prevention of cardiovascular events, with a concerning trend toward harm. This review outlines the lessons learned from the basic science, animal, observational, and randomized trials, and then summarizes yet-unanswered questions of hormone therapy and cardiovascular risk.

Animals↗

PubMed2006

Vascular endothelial dysfunction is associated with reversible myocardial perfusion defects in the absence of obstructive coronary artery disease.

BACKGROUND: The purpose of this study was to investigate whether endothelial dysfunction contributes to abnormal myocardial perfusion imaging (MPI) observed in patients without obstructive coronary artery disease (CAD). It is unclear whether reversible MPI defects detected in the absence of obstructive CAD represent underlying vascular pathology or are false-positive MPI results. Recent evidence suggests that coronary endothelial dysfunction might play a role in the pathogenesis of these defects. METHODS AND RESULTS: We prospectively recruited 36 patients with chest discomfort, reversible abnormalities on MPI, and nonobstructive or absent CAD (stenosis <50% on coronary angiography). The control group (n = 55) consisted of patients with chest discomfort and similar cardiac risk factors but with normal MPI findings. Vascular endothelial function was assessed in the brachial artery by ultrasound as the response to hyperemia and reported as percent flow-mediated dilation (FMD). Response to sublingual nitroglycerin was used as an indicator of endothelium-independent vasodilation. The patients with abnormal MPI findings and nonobstructive CAD had a significantly lower FMD (9.0% +/- 7.2%), indicating endothelial dysfunction, compared with those with similar risk factors and normal MPI findings (12% +/- 5.2%) (P = .03). Baseline brachial artery size and endothelium-independent dilation were similar between groups. On multivariate analysis, only endothelial dysfunction was predictive of reversible MPI defects. CONCLUSIONS: Patients with chest pain and reversible MPI defects but without obstructive CAD have lower FMD indicative of endothelial dysfunction, as compared with similar patients with normal MPI findings. The possibility of a causal link between reversible MPI defects and endothelial dysfunction needs further exploration.

Coronary Disease↗

PubMed2006

Estrogen replacement and cardiomyocyte protection.

The effects of estrogen on vascular function have been studied extensively; however, much less is known regarding the effect of estrogen on myocardial function and cardiomyocyte biology. We recently examined the effects of estrogen on infarct size and left ventricular remodeling after induction of myocardial infarction by permanent coronary ligation in ovariectomized female mice. These studies demonstrated that physiologic replacement with 17beta-estradiol (E(2)) reduced infarct size and reduced cardiomyocyte apoptosis at 24 and 72 hours post-myocardial infarction. In vivo, physiologic E(2) replacement rapidly activated the Akt signaling pathway within the myocardium. In vitro, physiologic concentrations of E(2) rapidly activated Akt via estrogen receptor alpha (ERalpha) and phosphoinositide-3 (PI3)-kinase-dependent mechanisms. Moreover, estrogen mitigated anthracycline-induced apoptosis in vitro via ER- and PI3-kinase-Akt-dependent mechanisms. Our data therefore support that estrogen favorably influences cardiomyocyte survival both in a coronary occlusion model in vivo and in cultured cardiomyocytes in vitro. Further work is necessary to more completely understand the complex effects of sex hormones on cardiomyocyte biology.

Animals↗

PubMed2006

High-density lipoprotein cholesterol-raising strategies.

There is a distinct inverse relationship between high-density lipoprotein cholesterol (HDL-C) and cardiovascular disease risk. HDL-C mediates cholesterol efflux from the vasculature and promotes anti-oxidant, anti-inflammatory, and anti-thrombotic effects. There are multiple lifestyle and therapeutic interventions that raise HDL-C, and there is increasing evidence that these interventions improve cardiovascular outcomes. Recent findings regarding the role of HDL-C in cholesterol metabolism offer new strategies designed to target atherosclerosis. This review highlights the utility of existing HDL-C-raising strategies and examines new potential therapies.

Apolipoprotein A-I↗

PubMed2006

Evaluation of peripheral vascular endothelial function with a portable ultrasound device.

Endothelial function can be assessed noninvasively by imaging the brachial artery with ultrasound before and during reactive hyperemia. However, the standard ultrasound equipment typically used for this purpose is limited by size and expense of the machinery. In this study, we compared the ability of a portable ultrasound device to standard ultrasound equipment to visualize the brachial artery for purposes of assessing peripheral vascular endothelial function. The portable device provided comparable imaging of the brachial artery at rest and during hyperemia to that of standard ultrasound technology. These findings support the feasibility of noninvasive evaluation of peripheral endothelial function in the ambulatory setting.

Adult↗

PubMed2005

Gender-based differences in brachial artery flow-mediated vasodilation as an indicator of significant coronary artery disease.

Ultrasound of the brachial artery is widely used to assess endothelial function, but whether brachial artery flow-mediated vasodilation (FMD) differs between women and men who have coronary artery disease (CAD) has not been examined. To investigate gender-based differences in brachial artery FMD as an indicator of significant CAD, FMD was measured in women and men outpatients who had CAD (coronary stenosis >50%, n = 64) and those who did not have significant CAD (n = 145). FMD in women who had CAD (n = 33, 9.1 +/- 0.8%) was higher than that in similarly aged men who had CAD (n = 31, 6.4 +/- 0.5%; p = 0.008). The FMD cutpoint that maximized sensitivity with least effect on specificity for screening CAD was 15% (91% sensitivity, 25% specificity) in women but 10% (90% sensitivity, 43% specificity) in men. If the cutpoint as defined in men were used to evaluate women, brachial artery ultrasound would fail to diagnose 42% of women who do not have significant CAD; thus, a higher FMD cutpoint is required to optimize the sensitivity of FMD for identifying women who have significant CAD compared with similarly aged men. In studies using FMD to evaluate cardiovascular risk, different standards should be applied for women and men.

Brachial Artery↗

PubMed2005

Estrogen receptor-alpha variants are associated with lipoprotein size distribution and particle levels in women: the Framingham Heart Study.

Plasma lipid profile is affected by endogenous estrogen levels and hormone replacement therapy (HRT). As plasma lipid concentrations have a significant heritable basis and the effects of both endogenous estrogen and use of HRT are mediated by estrogen receptors, we sought to investigate the relationships between polymorphisms in estrogen receptor-alpha (ESR1) and plasma lipid and lipoprotein concentrations. We analyzed data from 854 women (mean age 52+/-10 years) from the Framingham Heart Study. A TA repeat in the promoter region, c.30T>C in exon 1, c.454-397T>C, and c.454-351A>G in intron 1, all in linkage disequilibrium (LD), were significantly associated with low-density lipoprotein (LDL) particle size and concentration of small LDL particles. Women with the c.454-397C allele had larger LDL particle size (21.09+/-0.02 nm versus 21.01+/-0.03 nm, p=0.021) concurrent with lower small LDL particle concentration (0.47+/-0.02 mmol/L versus 0.58+/-0.03 mmol/L, p=0.008). Moreover, the TA[L]-c.30C-c.454-397C-c.454-351G haplotype (frequency, 32%) was associated with lower small LDL particle concentrations (-0.06+/-0.03 mmol/L change associated with each copy of this haplotype, p=0.011) when compared to the TA[S]-c.30T-c.454-397T-c.454-351A haplotype (frequency, 46%), where L and S are long and short TA repeats. Our results suggest that common ESR1 polymorphisms have a significant effect on lipoprotein metabolism in women.

Alleles↗

PubMed2005

Molecular and cellular basis of cardiovascular gender differences.

Cardiovascular diseases (CVDs), the major cause of morbidity and mortality for both men and women, occur uncommonly in premenopausal women, but their incidence rises sharply after the menopausal transition. Cardiovascular gender differences are apparent long before CVDs appear in men and women, and improved understanding of the biology underlying these differences has the potential to advance the diagnosis and treatment of CVDs in both sexes. This review considers gender differences in the molecular and cellular physiology of the heart and blood vessels in health and disease, highlighting understudied areas that can help resolve the current controversy regarding hormone replacement therapy and improve cardiovascular health in women.

Animals↗

PubMed2005

Modulator recognition factor 1, an AT-rich interaction domain family member, is a novel corepressor for estrogen receptor alpha.

Cardiovascular tissues are important targets of estrogen action. Vascular cells express the two known estrogen receptors (ERs), ERalpha and ERbeta, ligand-activated transcription factors that regulate gene transcription through interactions with both coactivator and corepressor molecules. To isolate ERalpha coregulators in vascular cells, we performed a yeast two-hybrid screen for ERalpha-interacting proteins using a human aorta library. Here we report the identification of modulator recognition factor 1 (MRF1) as an ERalpha-interacting corepressor protein. Full-length MRF1 binds to both the N terminus and the C terminus of ERalpha. ERalpha and MRF1 coimmunoprecipitate in an estradiol-independent manner, and recombinant ERalpha binds to both full-length and COOH-terminal MRF1 in the absence of estradiol. MRF1 also interacts in a ligand-dependent manner with thyroid receptor alpha, retinoid X receptor alpha, and androgen receptor, and in a ligand-independent manner with ERbeta and the retinoic acid receptor. MRF1 RNA is highly expressed in aorta, heart, skeletal muscle, and liver. MRF1 has intrinsic repressor activity in an in vitro GAL reporter assay. Transient transfection studies show that MRF1 represses transcription by ERalpha activated by estradiol in a dose-dependent manner, as well as by the selective ER modulators 4-hydroxy-tamoxifen and raloxifene. MRF1 repression is not influenced by pharmacological inhibition of histone deacetylase. These data identify MRF1 as a repressor of ERalpha-mediated transcriptional activation and support a role for MRF1 in regulating ER-dependent gene expression in cardiovascular and other cells.

Aorta↗

PubMed2005

The safety of rosuvastatin as used in common clinical practice: a postmarketing analysis.

BACKGROUND: Statins are currently the mainstay of dyslipidemia management for the primary and secondary prevention of cardiovascular disease. Controversial concerns about the safety of the newly marketed statin rosuvastatin have been raised on the basis of premarketing studies and a few postmarketing reports. METHODS AND RESULTS: We reviewed rosuvastatin-associated adverse events reported to the US Food and Drug Administration over its first year of marketing. On the basis of prescription data obtained from IMS Health, rates of adverse event reports (AERs) per million prescriptions were calculated. Rates of rosuvastatin-associated AERs over its first year of marketing were compared with those seen with atorvastatin, simvastatin, and pravastatin over the concurrent timeframe and during their respective first years of marketing. Comparison was also made to the first year of marketing of cerivastatin. The primary analysis examined the composite end point of AERs of rhabdomyolysis, proteinuria, nephropathy, or renal failure. With either timeframe comparison, rosuvastatin was significantly more likely to be associated with the composite end point of rhabdomyolysis, proteinuria, nephropathy, or renal failure AERs. Reported cases of rhabdomyolysis, proteinuria, or renal failure tended to occur early after the initiation of therapy and at relatively modest doses of rosuvastatin. The increased rate of rosuvastatin-associated AERs relative to other widely used statins was also observed in secondary analyses when other categories of AERs were examined, including adverse events with serious outcomes, liver toxicity, and muscle toxicity without rhabdomyolysis. CONCLUSIONS: The present analysis supports concerns about the relative safety of rosuvastatin at the range of doses used in common clinical practice in the general population.

Consumer Product Safety↗

PubMed2005

p38 mitogen-activated protein kinase activates eNOS in endothelial cells by an estrogen receptor alpha-dependent pathway in response to black tea polyphenols.

Black tea has been shown to improve endothelial function in patients with coronary artery disease and recent data indicate the polyphenol fraction of black tea enhances endothelial nitric oxide synthase (eNOS) activity through p38 MAP kinase (p38 MAPK) activation. Because the mechanisms for this phenomenon are not yet clear, we sought to elucidate the signaling events in response to black tea polyphenols. Bovine aortic endothelial cells (BAECs) exposed to black tea polyphenols demonstrated eNOS activation that was inhibited by the estrogen receptor (ER) antagonist ICI 182,780, and siRNA-mediated silencing of ER expression. Consistent with this observation, black tea polyphenols induced time-dependent phosphorylation of ERalpha on Ser-118 that was inhibited by ICI 182,780. Phosphorylation of ERalpha on Ser-118 was due to p38 MAP kinase (p38 MAPK) as, it was inhibited by SB203580 and overexpression of dominant-negative p38alpha MAPK. Conversely, constitutively active MKK6 induced p38 MAPK activation that recapitulated the effects of polyphenols by inducing ERalpha phosphorylation and downstream activation of Akt, and eNOS. The key role of ERalpha Ser-118 phosphorylation was confirmed in eNOS-transfected COS-7 cells, as polyphenol-induced eNOS activation required cotransfection with ERalpha subject to phosphorylation at Ser-118. This residue appeared critical for functional association of ERalpha with p38 MAPK as ERalpha with Ser-118 mutated to alanine could not form a complex with p38 MAPK. These findings suggest p38 MAP kinase-mediated eNOS activation requires ERalpha and these data uncover a new mechanism of ERalpha activation that has broad implications for NO bioactivity and endothelial cell phenotype.

Animals↗

PubMed2005

Ventricular assist device therapy normalizes inducible nitric oxide synthase expression and reduces cardiomyocyte apoptosis in the failing human heart.

OBJECTIVES: We examined the effect of mechanical unloading with ventricular assist device (VAD) therapy on myocardial inducible nitric oxide synthase (iNOS) expression and cardiomyocyte apoptosis in patients with end-stage heart failure (HF). BACKGROUND: Despite advances in medical therapy, HF continues to be a progressive and ultimately fatal disorder. High levels of iNOS expression are present in the myocardium of failing hearts, suggesting a potential role for iNOS in HF progression. METHODS: Inducible NOS protein expression was analyzed by Western blotting and cardiomyocyte apoptosis by terminal deoxynucleotidyltransferase dUTP nick end-labeling (TUNEL) in myocardial samples from failing hearts. Included in these analyses were tissues from 9 patients at the time of transplantation (HF-transplant group), 10 patients at the time of VAD insertion (pre-VAD group), and 11 patients undergoing transplant after VAD support (post-VAD group). Seven control samples were obtained at autopsy. RESULTS: Low or undetectable levels of iNOS were present in controls (0.005 +/- 0.002). The HF-transplant and pre-VAD myocardial specimens exhibited a marked increase in iNOS expression (1.48 +/- 0.34 and 1.29 +/- 0.26, respectively; p < 0.01 for both vs. controls). The increase in iNOS expression was reversed in the post-VAD group (0.36 +/- 0.16; p < 0.01 vs. HF-transplant and pre-VAD groups). The rate of TUNEL-positive cardiomyocytes was high in the pre-VAD group and significantly lower in the post-VAD group (0.64 +/- 0.15% in pre-VAD group and 0.16 +/- 0.07% in post-VAD group; p < 0.01). The iNOS levels correlated significantly with cardiomyocyte apoptosis (r = 0.66, p < 0.01). CONCLUSIONS: Therapy with VAD normalizes iNOS expression in association with diminished cardiomyocyte apoptosis in the failing heart. Further work is required to define whether a causal relationship exists between iNOS and cardiomyocyte apoptosis.

Adult↗

PubMed2005

Comparison of flow-mediated dilatation of the brachial artery in coronary patients with low-density lipoprotein cholesterol levels <80 mg/dl versus patients with levels 80 to 100 mg/dl.

Testing of peripheral vascular endothelial function was performed in subjects who had coronary artery disease and a low-density lipoprotein (LDL) cholesterol level <100 mg/dl. LDL cholesterol was an independent predictor of flow-mediated dilation of the brachial artery (p = 0.010). The 63 subjects who had an LDL cholesterol level <80 mg/dl had better endothelial function (flow-mediated dilation 8.4 +/- 3.8%) than did 47 subjects whose level of LDL cholesterol was 80 to 100 mg/dl (flow-mediated dilation 6.8 +/- 4.0%, p = 0.03). The beneficial effects of LDL cholesterol levels <80 mg/dl on endothelial function were more apparent in subjects who had low levels of high-density lipoprotein cholesterol than in those who had normal levels. These data support recent reports that decreasing levels of LDL cholesterol below those currently recommended provides additional benefits and suggest that this benefit may be due in part to increased endothelial function.

Brachial Artery↗

PubMed2005

Peripheral vascular endothelial function correlates with exercise capacity in women.

BACKGROUND: Vascular endothelial function has been observed to correlate with exercise capacity in predominantly male populations. Gender-based differences exist in the clinical course of coronary artery disease, and previous studies indicate that estrogen may influence endothelial function. These observations raise the possibility that the relationship between endothelial function and exercise capacity in women may differ from that in men. HYPOTHESIS: This study aimed to determine whether peripheral vascular endothelial function correlates with exercise capacity in women. METHODS: Women who were referred for clinically indicated exercise testing with technetium-99 myocardial perfusion imaging were consecutively recruited. To ensure a population free of exercise limitation due to ischemic heart disease, women without myocardial perfusion defects were included for analysis in this study (n = 105). Endothelial function was assessed by brachial artery ultrasound flow-mediated vasodilation (FMD). Exercise capacity was defined as the duration of exercise on a symptom-limited Bruce protocol. RESULTS: Mean FMD was 11.8 +/- 0.6%, and median FMD was 12%. Subjects with an FMD less than the median of 12% had a significantly shorter exercise time than those with FMD > or = 12% (411 +/- 17 vs. 482 +/- 24 s, p = 0.014). There was a significant correlation between FMD and exercise time (r = 0.34, p < 0.001). Age and body mass index were additional predictors of exercise time; however, the relationship between FMD and exercise time was independent of these variables. CONCLUSION: Brachial artery FMD correlates with exercise capacity in women, even in the absence of ischemic heart disease.

Adult↗

PubMed2005

Association of estrogen receptor beta gene polymorphisms with left ventricular mass and wall thickness in women.

BACKGROUND: Left ventricular (LV) hypertrophy is a significant risk factor for cardiovascular disease. Given sex-based differences in cardiac structure and remodeling, we hypothesized that variation in estrogen pathway genes might be associated with alteration of LV structure. METHODS: We studied 1249 unrelated individuals, 547 men and 702 women (mean age 59 years) from the Framingham Heart Study. Eight single nucleotide polymorphisms in the genes for estrogen receptor alpha and estrogen receptor beta (ESR2) were tested for association with 5 LV measures: LV mass (LVM), LV wall thickness (LVWT), LV internal diameter at end-diastole and end-systole, and fractional shortening. Sex-specific multiple regression analyses were performed adjusting for age, weight, height, systolic and diastolic blood pressure, hypertension treatment, diabetes, and in women, menopausal status. RESULTS: In men, there was no evidence of association between the estrogen pathway polymorphisms tested and LV structure or function. In women, however, two polymorphisms, ESR2 rs1256031 and ESR2 rs1256059, in linkage disequilibrium with one another, were associated with LVM and LVWT (P = .0007 to .03); the association was most pronounced in those women with hypertension (P = .0006 to .01). The association did not appear to be explained by variation in blood pressure, plasma lipoprotein levels, or hyperglycemia. CONCLUSIONS: The ESR2 polymorphisms are associated with LV structural differences in women with hypertension in a community-based population. These data are consistent with the hypothesis that genetic factors may mediate part of the observed sex-based differences in LV structure and remodeling.

Aged↗