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Usefulness of clopidogrel to protect against diabetes-induced vascular damage

McClung, John A; Kruger, Adam L; Ferraris, Ambra; Vanella, Luca; Tsenovoy, Petr; Weiss, Melvin B; Abraham, Nader G
Clopidogrel enhances the levels of endothelial nitric oxide and prostacyclin in tissue culture. We have previously described a marked increase in circulating endothelial cells (CECs), an ex vivo indicator of vascular injury, in patients with type 2 diabetes mellitus. We hypothesized that clopidogrel treatment would result in a decrease in CEC number and increased activity of endothelial progenitor cell recruitment signaling pathways in diabetic patients. CECs were isolated from the peripheral blood of 9 patients with type 2 diabetes using anti-CD146-coated Dynabeads. The cells were stained with acridine orange and counted by fluorescence microscopy. Endothelial progenitor cells were isolated in a similar fashion using anti-CD34 and anti-CD133 and assayed for expression of phosphorylated Akt and phosphorylated adenosine monophosphate kinase. The patients were then treated with clopidogrel 75 mg/day for 30 days, after which repeat blood specimens were analyzed. As previously observed, diabetic patients had an elevated number of CECs (mean 79 +/- 15 cells/ml peripheral blood), which was reduced by clopidogrel treatment (mean 10 +/- 4 cells/ml; p <0.001). This was associated with a significant increase in the expression of both phosphorylated Akt and phosphorylated adenosine monophosphate kinase (p
PMID: 20346323
ISSN: 0002-9149
CID: 364562

Prevalence of complications during implantation and during 38-month follow-up of 1060 consecutive patients with implantable cardioverter-defibrillators

Tsai, Fausan S; Aronow, Wilbert S; Devabhaktuni, Srikala; Desai, Harit; Kruger, Adam; Lai, Hoang M; Frishman, William H; Cohen, Martin; Sorbera, Carmine
During implantation and during 38-month follow-up of 1060 consecutive patients who had implantable cardioverter-defibrillators, complications occurred in 60 (5.7%) of 1060 patients. These complications consisted of fractured leads requiring lead revision in 36 (3.4%) patients, lead infection requiring antibiotics in 5 (0.5%) patients, device replacement because of malfunction in 5 (0.5%) patients, repositioning of leads in 3 (0.3%) patients, a hematoma at the time of implantation in 3 (0.3%) patients, pneumothorax at the time of implantation in 2 (0.2%) patients, repair of a defective generator in 1 (0.1%) patient, replacement of the device because of atrophy of the skin over the device in 1 (0.1%) patient, a transient ischemic attack because of atrial fibrillation developing during implantation in 1 (0.1%) patient, device replacement because of a recall from Guidant in 1 (0.1%) patient, pocket revision because of pain when lying on the side of the pacemaker in 1 (0.1%) patient, and pacemaker infection in 1 (0.1%) patient.
PMID: 19262366
ISSN: 1536-3686
CID: 5019412

Prevalence of appropriate cardioverter-defibrillator shocks in 1038 consecutive patients with implantable cardioverter-defibrillators

Kruger, Adam; Aronow, Wilbert S; Lai, Hoang; Desai, Harit; Singla, Atul; Frishman, William H; Cohen, Martin; Sorbera, Carmine
During a 33-month follow-up of 1038 consecutive patients who had implantable cardioverter-defibrillators, appropriate shocks occurred in 329 of 1038 patients (32%). Appropriate shocks occurred in 101 of 380 patients (27%) treated with beta-adrenergic blockers alone; in 31 of 95 patients (33%) treated with amiodarone alone; in 39 of 149 patients (26%) treated with beta-blockers plus amiodarone; in 11 of 28 patients (39%) treated with sotalol alone; and in 147 of 386 patients (38%) treated with no beta-blockers, amiodarone, or sotalol (P < 0.001 comparing patients treated with beta-adrenergic blockers alone with patients treated with no beta-blockers, amiodarone, or sotalol; and P < 0.01 comparing patients treated with beta-blockers plus amiodarone with patients treated with no beta-blockers, amiodarone, or sotalol). In conclusion, patients having implantable cardioverter-defibrillators should also be treated with beta-adrenergic blockers to reduce the frequency of appropriate shocks.
PMID: 19617719
ISSN: 1536-3686
CID: 5019422

L-4F treatment reduces adiposity, increases adiponectin levels, and improves insulin sensitivity in obese mice

Peterson, Stephen J; Drummond, George; Kim, Dong Hyun; Li, Ming; Kruger, Adam L; Ikehara, Susumu; Abraham, Nader G
We hypothesized that the apolipoprotein mimetic peptide L-4F, which induces arterial anti-oxidative enzymes and is vasoprotective in a rat model of diabetes, would ameliorate insulin resistance and diabetes in obese mice. L-4F (2 mg/kg/d) administered to ob/ob mice for 6 weeks limited weight gain without altering food intake, decreased visceral (P < 0.02) and subcutaneous (P < 0.045) fat content, decreased plasma IL-1beta and IL-6 levels (P < 0.05) and increased insulin sensitivity, resulting in decreased glucose (P < 0.001) and insulin (P < 0.036) levels. In addition, L-4F treatment increased aortic and bone marrow heme oxygenase (HO) activity and decreased aortic and bone marrow superoxide production (P < 0.001). L-4F treatment increased serum adiponectin levels (P < 0.037) and decreased adipogenesis in mouse bone marrow (P < 0.039) and in cultures of human bone marrow-derived mesenchymal stem cells (P < 0.022). This was manifested by reduced adiposity, improved insulin sensitivity, improved glucose tolerance, increased plasma adiponectin levels, and reduced IL-1beta and IL-6 levels in obese mice. This study highlights the existence of a temporal relationship between HO-1 and adiponectin that is positively affected by L-4F in the ob/ob mouse model of diabetes, resulting in the amelioration of the deleterious effects of diabetes.
PMID: 18426778
ISSN: 0022-2275
CID: 364752

Effect of beta blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and statins on mortality in patients with implantable cardioverter-defibrillators

Lai, Hoang M; Aronow, Wilbert S; Kruger, Adam; Desai, Harit; Amin, Harshad; Frishman, William H; Cohen, Martin; Sorbera, Carmine
Nine hundred sixty-five patients (mean age 70 years) with implantable cardioverter-defibrillator were followed for 32 +/- 33 months for all-cause mortality. Death occurred in 73 of 515 patients (13%) treated with beta blockers (group 1), in 84 of 494 patients (17%) treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (group 2), in 56 of 402 patients (14%) treated with statins (group 3), in 40 of 227 patients (18%) treated with amiodarone (group 4), in 5 of 26 patients (19%) treated with sotalol (group 5), and in 64 of 265 patients (24%) treated with no beta blocker, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, statin, amiodarone, or sotalol (group 6) (p <0.001 for group 1 vs group 6 and group 3 vs group 6, p <0.02 for group 2 vs group 6). In conclusion, patients with implantable cardioverter-defibrillators should be treated with beta blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and statins to reduce mortality.
PMID: 18572039
ISSN: 0002-9149
CID: 5019402

Long-term treatment with the apolipoprotein A1 mimetic peptide increases antioxidants and vascular repair in type I diabetic rats

Peterson, Stephen J; Husney, Daniel; Kruger, Adam L; Olszanecki, Rafal; Ricci, Francesca; Rodella, Luigi F; Stacchiotti, Alessandra; Rezzani, Rita; McClung, John A; Aronow, Wilbert S; Ikehara, Susumu; Abraham, Nader G
Apolipoprotein A1 mimetic peptide (D-4F), synthesized from D-amino acid, enhances the ability of high-density lipoprotein to protect low-density lipoprotein (LDL) against oxidation in atherosclerotic disease. Using a rat model of type I diabetes, we investigated whether chronic use of D-4F would lead to up-regulation of heme oxygenase (HO)-1, endothelial cell marker (CD31(+)), and thrombomodulin (TM) expression and increase the number of endothelial progenitor cells (EPCs). Sprague-Dawley rats were rendered diabetic with streptozotocin (STZ) and either D-4F or vehicle was administered, by i.p. injection, daily for 6 weeks (100 microg/100 g b.wt.). HO activity was measured in liver, kidney, heart, and aorta. After 6 weeks of D-4F treatment, HO activity significantly increased in the heart and aorta by 29 and 31% (p < 0.05 and p < 0.49), respectively. Long-term D-4F treatment also caused a significant increase in TM and CD31(+) expression. D-4F administration increased antioxidant capacity, as reflected by the decrease in oxidized protein and oxidized LDL, and enhanced EPC function and/or repair, as evidenced by the increase in EPC endothelial nitric-oxide synthase (eNOS) and prevention of vascular TM and CD31(+) loss. In conclusion, HO-1 and eNOS are relevant targets for D-4F and may contribute to the D-4F-mediated increase in TM and CD31(+), the antioxidant and anti-inflammatory properties, and confers robust vascular protection in this animal model of type 1 diabetes.
PMID: 17488882
ISSN: 0022-3565
CID: 364832

Up-regulation of heme oxygenase provides vascular protection in an animal model of diabetes through its antioxidant and antiapoptotic effects

Kruger, Adam L; Peterson, Stephen J; Schwartzman, Michal L; Fusco, Heidi; McClung, John A; Weiss, Melvin; Shenouda, Sylvia; Goodman, Alvin I; Goligorsky, Michael S; Kappas, Attallah; Abraham, Nader G
Heme oxygenase (HO) plays a critical role in the regulation of cellular oxidative stress. The effects of the reactive oxygen species scavenger ebselen and the HO inducers cobalt protoporphyrin and stannous chloride (SnCl(2)) on HO protein levels and activity, indices of oxidative stress, and the progression of diabetes were examined in the Zucker rat model of type 2 diabetes. The onset of diabetes coincided with an increase in HO-1 protein levels and a paradoxical decrease in HO activity, which was restored by administration of ebselen. Up-regulation of HO-1 expressed in the early development of diabetes produced a decrease in oxidative/nitrosative stress as manifested by decreased levels of 3-nitrotyrosine, superoxide, and cellular heme content. This was accompanied by a decrease in endothelial cell sloughing and reduced blood pressure. Increased HO activity was also associated with a significant increase in the antiapoptotic signaling molecules Bcl-xl and phosphorylation of p38-mitogen-activated protein kinase but no significant increases in Bcl-2 or BAD proteins. In conclusion, 3-nitrotyrosine, cellular heme, and superoxide, promoters of vascular damage, are reduced by HO-1 induction, thereby preserving vascular integrity and protecting cardiac function involving an increase in antiapoptotic proteins.
PMID: 16959961
ISSN: 0022-3565
CID: 364212

Antioxidant mechanism of heme oxygenase-1 involves an increase in superoxide dismutase and catalase in experimental diabetes

Turkseven, Saadet; Kruger, Adam; Mingone, Christopher J; Kaminski, Pawel; Inaba, Muneo; Rodella, Luigi F; Ikehara, Susumu; Wolin, Michael S; Abraham, Nader G
Increased heme oxygenase (HO)-1 activity attenuates endothelial cell apoptosis and decreases superoxide anion (O2-) formation in experimental diabetes by unknown mechanisms. We examined the effect of HO-1 protein and HO activity on extracellular SOD (EC-SOD), catalase, O2-, inducible nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS) levels and vascular responses to ACh in control and diabetic rats. Vascular EC-SOD and plasma catalase activities were significantly reduced in diabetic compared with nondiabetic rats (P < 0.05). Upregulation of HO-1 expression by intermittent administration of cobalt protoporphyrin, an inducer of HO-1 protein and activity, resulted in a robust increase in EC-SOD but no significant change in Cu-Zn-SOD. Administration of tin mesoporphyrin, an inhibitor of HO-1 activity, decreased EC-SOD protein. Increased HO-1 activity in diabetic rats was associated with a decrease in iNOS but increases in eNOS and plasma catalase activity. On the other hand, aortic ring segments from diabetic rats exhibited a significant reduction in vascular relaxation to ACh, which was reversed with cobalt protoporphyrin treatment. These data demonstrate that an increase in HO-1 protein and activity, i.e., CO and bilirubin production, in diabetic rats brings about a robust increase in EC-SOD, catalase, and eNOS with a concomitant increase in endothelial relaxation and a decrease in O2-. These observations in experimental diabetes suggest that the vascular cytoprotective mechanism of HO-1 against oxidative stress requires an increase in EC-SOD and catalase.
PMID: 15821039
ISSN: 0363-6135
CID: 365032

D-4F induces heme oxygenase-1 and extracellular superoxide dismutase, decreases endothelial cell sloughing, and improves vascular reactivity in rat model of diabetes

Kruger, Adam L; Peterson, Stephen; Turkseven, Saadet; Kaminski, Pawel M; Zhang, Frank Fan; Quan, Shuo; Wolin, Michael S; Abraham, Nader G
BACKGROUND: Apolipoprotein A1 mimetic peptide, synthesized from D-amino acid (D-4F), enhances the ability of HDL to protect LDL against oxidation in atherosclerotic animals. METHODS AND RESULTS: We investigated the mechanisms by which D-4F provides antioxidant effects in a diabetic model. Sprague-Dawley rats developed diabetes with administration of streptozotocin (STZ). We examined the effects of daily D-4F (100 microg/100 g of body weight, intraperitoneal injection) on superoxide (O2-), extracellular superoxide dismutase (EC-SOD), vascular heme oxygenase (HO-1 and HO-2) levels, and circulating endothelial cells in diabetic rats. In response to D-4F, both the quantity and activity of HO-1 were increased. O2- levels were elevated in diabetic rats (74.8+/-8x10(3) cpm/10 mg protein) compared with controls (38.1+/-8x10(3) cpm/10 mg protein; P<0.01). D-4F decreased O2- levels to 13.23+/-1x10(3) (P<0.05 compared with untreated diabetics). The average number of circulating endothelial cells was higher in diabetics (50+/-6 cells/mL) than in controls (5+/-1 cells/mL) and was significantly decreased in diabetics treated with D-4F (20+/-3 cells/mL; P<0.005). D-4F also decreased endothelial cell fragmentation in diabetic rats. The impaired relaxation typical of blood vessels in diabetic rats was prevented by administration of D-4F (85.0+/-2.0% relaxation). Western blot analysis showed decreased EC-SOD in the diabetic rats, whereas D-4F restored the EC-SOD level. CONCLUSIONS: We conclude that an increase in circulating endothelial cell sloughing, superoxide anion, and vasoconstriction in diabetic rats can be prevented by administration of D-4F, which is associated with an increase in 2 antioxidant proteins, HO-1 and EC-SOD.
PMID: 15939814
ISSN: 0009-7322
CID: 365002

Overexpression of human heme oxygenase-1 attenuates endothelial cell sloughing in experimental diabetes

Abraham, Nader G; Rezzani, Rita; Rodella, Luigi; Kruger, Adam; Taller, Derek; Li Volti, Giovanni; Goodman, Alvin I; Kappas, Attallah
Heme oxygenase (HO)-1 represents a key defense mechanism against oxidative injury. Hyperglycemia produces oxidative stress and various perturbations of cell physiology. The effect of streptozotocin (STZ)-induced diabetes on aortic HO activity, heme content, the number of circulating endothelial cells, and urinary 8-epi-isoprostane PGF2alpha (8-Epi) levels in control rats and rats overexpressing or underexpressing HO-1 was measured. HO activity was decreased in hyperglycemic rats. Hyperglycemia increased urinary 8-Epi, and this increase was augmented in rats underexpressing HO-1 and diminished in rats overexpressing HO-1. The number of detached endothelial cells and O2- formation increased in diabetic rats and in hyperglycemic animals underexpressing HO-1 and decreased in diabetic animals overexpressing HO-1 compared with controls. These data demonstrate that HO-1 gene transfer in hyperglycemic rats brings about a reduction in O2- production and a decrease in endothelial cell sloughing. Upregulation of HO-1 decreases oxidant production and endothelial cell damage and shedding and may attenuate vascular complications in diabetes.
PMID: 15284058
ISSN: 0363-6135
CID: 365072