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Biomedical subjects

M Maiello

Publications and source records attributed to M Maiello.

At least 19 recordsLinked to original sources
PubMed2006

[Hypercoagulability during pregnancy: evidences for a thrombophilic state].

AIM: The development of thrombotic disorders is a major threat for young women during pregnancy. It is one of the main causes of pregnancy-related disorders, which may also result in harm for the conceptus. Successful pregnancies require an even balance of coagulation and fibrinolysis, in order to secure stabilization of the basal plate as well as adequate placental perfusion. Broad spectrum assays which measure a range of thrombin/fibrin formation in serum have become an established means of identifying activation of blood coagulation and/or fibrinolysis. There is considerable interest in the application of these assays to the diagnosis of other hypercoagulable states, such as thrombophilia during pregnancy. We investigated coagulation/fibrinolysis parameters for significant differences between pregnant women during their gestation (first, second and third trimester) with or without pregnancy loss and healthy nonpregnant women. METHODS: Thirty-nine pregnant women, aged 24-39 years, were studied. They were subdivided according to pregnancy trimester: 15 patients in the first trimester; 13 in the second and 11 in the third. The selection of patients was carried out in cooperation with the Transfusion Center of the Second University of Naples in order to obtain a homogeneous sample group. The control group included 400 healthy patients. Biochemical and blood coagulation tests were performed for each patient and the results obtained were compared with the control group. RESULTS: A decrease in free protein S (PS) and fibrinolysis (t-PA/PAI-1) activities and an increase in Factor VII, Factor VIII, prothrombin fragment 1+2 (F1+2), D-dimer (D-dimer) were observed in pregnant women during the follow-up of gestation. However, there were statistical differences between the groups of women with one or more pregnancy loss where it was found the lowest values in t-PA and PAI and the highest values in FVII and F1+2. Among subjects with more than one abortion, coagulation/fibrinolysis derangements before the partum were more prominent. A significant association exists between consecutive recurrent abortions and pregnancy complications such as placental abruption, hypertensive disorders and CS. This association persists after controlling for variables considered to coexist with recurrent abortions. CONCLUSIONS: These findings suggest that an excessive hypercoagulable state is associated with the termination of pregnancy resulting into a moderate risk for thrombosis during the different trimesters of pregnancy. The follow-up of fibrinolytic markers could represent a useful diagnostic tool for termination of pregnancy.

Blood Coagulation↗
PubMed2004

[Arrhythmic risk in essential hypertension: late potentials].

AIM: A higher incidence of cardiac death exists in patients with essential hypertension, and it is higher still in those with ventricular arrhythmia. The purpose of noninvasive diagnostic imaging in hypertensive patients is to determine those with a greater risk for arrhythmia. In previous studies on hypertension, one of the inclusion criteria is diastolic blood pressure <95 mmHg, which, however, is a low selectivity criterion. Instead, our study emphasizes the need to evaluate the incidence of ventricular arrhythmia in hypertensive patients not yet receiving drug therapy and to formulate the diagnosis based on 24-h ambulatory arterial blood pressure monitoring, which represents a more selective criterion than the diastolic pressure value proposed by the World Health Organization (WHO). METHODS: A total of 128 consecutive patients with essential hypertension classified according to WHO criteria underwent 24-h monitoring, 85 (66.4%) of which presented with a mean 24-h arterial pressure >135/85 mmHg. These patients were then evaluated using mono- and two-dimensional echocardiography and 24-h dynamic Holter monitoring to detect arrhythmias and the presence of left ventricular later potentials. RESULTS: Left ventricular hypertrophy was present in 60 (70.6%) patients and absent in 25 (29.4%). Based on the Lown classification of ventricular arrhythmia, 20 (23.5%) patients had Grade I arrhythmia, 5 (5.9%) Grade II, 4 (4.7%) Grade III, 9 (10.6%) Grade IVA, 20 (23.5%) Grade IVB, 12 (14.1%) Grade V, 15 (17.6%) clinically unremarkable arrhythmia, and 17 (20%) had late potentials because they tested positive to at least 2 out of three criteria, and 2 patients were positive to all 3 criteria. CONCLUSION: Our study findings demonstrated a significant correlation between left ventricular hypertrophy and grade of arrhythmia (r=0.552; p<0.0001) and late potentials (r=0.405; p<0.001). The presence of late potentials was also found to correlate significantly with grade of arrhythmia (r=0.593; p<0.001). These patients present with a more severe stage of the disease and should therefore receive more aggressive treatment to prevent sudden cardiac death resulting from arrhythmia.

Adult↗
PubMed2003

Heat-shock protein 70 favours human liver recovery from ischaemia-reperfusion.

BACKGROUND: Pringle's manoeuvre controls excessive bleeding, but results in ischaemia-reperfusion injury during liver surgery. Activation of the heat-shock protein system of cell defense has been demonstrated after ischaemia-reperfusion injury in animal tissues. The aim of the present study was to determine whether the ischaemia-reperfusion accompanying hepatic surgery induces heat-shock protein 70 (HSP70) in human liver and whether the induction of HSP70 is related to the recovery of liver function. METHODS: Heat-shock protein 70 and gamma-actin mRNAs were assayed in the liver biopsies of 10 subjects undergoing partial hepatectomy for localized lesions. Measurements were performed before the Pringle's manoeuvre and at the end of the surgery. Transaminases and fibrinogen were measured before and at 12, 24 and 36 h following hepatectomy. RESULTS: After an average 40 +/- 8-min period of warm ischaemia, a significant increase of HSP70 mRNA (187 +/- 67%, 2P < 0.05) was observed. The acute increase of HSP70 mRNA correlates with the decrease of transaminases (AST: rs -0.964, ALT: rs -0.891, P < 0.002) and the increase of fibrinogen (rs -0.7, P < 0.02) observed between 12 and 24 h following surgery. CONCLUSIONS: Heat-shock protein 70 is induced by ischaemia-reperfusion injury in human liver. Its induction seems to have beneficial effects, including a prompt reduction of transaminases and a rapid recovery of fibrinogen synthesis.

Analysis of Variance↗
PubMed2002

Cooperative inhibitory effect of ZD1839 (Iressa) in combination with trastuzumab (Herceptin) on human breast cancer cell growth.

BACKGROUND: Co-expression of the epidermal growth factor receptor (EGFR) and of ErbB-2 is found in a subset of primary human breast cancer. MATERIALS AND METHODS: The antiproliferative effects of anti-EGFR and anti-ErbB-2 agents were evaluated using a monolayer assay. The effects of these agents on the activation of EGFR, ErbB-2, AKT and p42/p44 MAP kinases (MAPK) were investigated by western blot analysis. RESULTS: We found that both ZD1839 (Iressa), a specific EGFR tyrosine kinase inhibitor, and trastuzumab (Herceptin) (TRA), a humanized anti-ErbB-2 monoclonal antibody, were able to inhibit the growth of SK-Br-3 and BT-474 breast carcinoma cells, which express both EGFR and ErbB-2. Treatment of breast carcinoma cells with a combination of ZD1839 and TRA resulted in a synergistic inhibitory effect. Treatment of SK-Br-3 cells with ZD1839 produced a significant, dose-dependent reduction of the tyrosine phosphorylation of both EGFR and ErbB-2. Phosphorylation of MAPK and AKT were significantly reduced in SK-Br-3 cells following treatment with ZD1839, whereas treatment with TRA produced a reduction of AKT but not MAPK phosphorylation. Finally, treatment with ZD1839, but not with TRA, produced a significant increase in fragmented DNA in breast carcinoma cells. However, a more pronounced increase in the levels of fragmented DNA was observed following combined treatment with ZD1839 and TRA. CONCLUSIONS: These data suggest that combined treatment with drugs that target EGFR and ErbB-2 might result in an efficient inhibition of tumor growth in those breast carcinoma patients whose tumors co-express both receptors.

Antibodies, Monoclonal↗
PubMed2001

Increased prevalence of microthromboses in retinal capillaries of diabetic individuals.

In diabetic retinopathy, capillary nonperfusion and eventual obliteration can lead to retinal ischemia and sight-threatening neovascularization. The occurrence of retinal microthrombosis in human diabetes has long been suspected and occasionally observed but never systematically demonstrated. We used trypsin digestion to isolate the intact vascular network from retinas obtained postmortem from nine diabetic donors (age 64 +/- 11 years, duration of diabetes 6 +/- 4 years; mean +/- SD) and eight age-matched nondiabetic donors. Topographically matched sectors (each one-sixth of retina) of diabetic and nondiabetic retinas were tested sequentially with antibodies to fibrin cross-linking factor XIII and platelet glycoprotein (GP)-IIIa to identify fibrin-platelet thrombi. In some trypsin digests, we also examined vascular cell apoptosis. The retina from a nondiabetic donor, 24 years of age, who had died of trauma, was used to exclude confounding influences caused by the postmortem period. When compared with those of nondiabetic donors, the retinas of diabetic donors showed double the number of capillary segments with colocalized immunostaining for factor XIII and GPIIIa (P = 0.02). The total area of the positive segments was fourfold greater in the diabetic than in the nondiabetic donors (P = 0.02) and correlated with the duration of diabetes (r = 0.71, P < 0.05). Large thrombi were six times more frequent in the diabetic donors (P = 0.03), and there was a significant topographical association of microthrombosis with apoptotic cells in both diabetic and nondiabetic vessels (P = 0.0001). Hence, diabetes of short duration was found to be associated with a greater than normal number and size of platelet-fibrin thrombi in the retinal capillaries. These thrombi can contribute to capillary obliteration and retinal ischemia and may be a practical target for early drug intervention.

Adult↗
PubMed2001

[Silent ischemia and ventricular arrhythmias in essential hypertension].

BACKGROUND: Silent ischemia episodes rate is 4-5% among over fifty aged people. Patients affected by hypertension have higher coronary artery disease rate than people with normal blood pressure. An increased mortality is present among patients affected by essential hypertension, especially if affected by silent ischemia and /or ventricular arrhythmias. In all previous study about hypertension, the inclusion criterion was a diastolic blood pressure >95 mmHg, that is a low selective one. The aim of study is to evaluate ventricular arrhythmias rate, in hypertensive patients, without pharmacological therapy, and diagnosed by 24 hours ambulatory blood pressure monitoring (ABPM), so using a more selective criterion than WHO rules. METHODS: 128 consecutive patients with hypertension diagnosis by WHO rules, were screened for 24 hours ambulatory blood pressure measurement (ABPM); 85 of them (66.4%) had 24 hours mean blood pressure >135/85 mmHg. These 85 patients were screened for M-mode, B-mode echocardiography and 24 hours electrocardiogram monitoring by Holter. RESULTS: Sixty patients (70.6%) were affected by left ventricular hypertrophy, 25 were free (29.4%) According to the Lown and Wolf classification for ventricular arrhythmias 20 patients (23.5%) had a Grade I arrhythmia, 5 (5.9%) had a Grade II, 4 (4.7%) had a Grade III, 9 (10.6%) had a Grade IV A, 20 (23.5%) had a Grade IV B, 12 (14.2%) had a Grade V and 15 patients (17.6%) were free from premature ventricular complexes. 40 patients (47%) had one or more ST depression episodes longer than 60 . The range of episodes number is 1-22, mean 6.8; their duration range is 1-16 minutes, mean 7.6 minutes. In our study, left ventricular hypertrophy correlate significantly with arrhythmia Lown score, r=0.552 for p<0.0001 and also with silent ischemia as ST depression r=0.51, p<0.004. The correlation, between arrhythmia score and ST depression, r=0.042, p<0.021 is not highly significant. CONCLUSIONS: The conclusion is drawn that using a more selective criterion for the diagnosis of hypertension, it is possible to identify patients affected by a more severe stage of disease, and detect them for primary prevention of coronary events.

Adult↗
PubMed2000

Ventricular arrhythmias and left ventricular hypertrophy in essential hypertension.

BACKGROUND: Patients with essential hypertension and/or left ventricular hypertrophy and ventricular arrhythmias suffer from an increased mortality rate. In all previous studies on hypertension, the criterion for inclusion was diastolic blood pressure > 95 mmHg. This is a low selective threshold. Our study attempted to evaluate the incidence of ventricular arrhythmia in hypertensive patients not receiving pharmacological treatment and diagnosed by 24-h ambulatory blood pressure monitoring (ABPM), therefore using a more selective criterion than WHO guidelines. METHODS: Hundred-twenty-height consecutive patients with hypertension diagnosed on the basis of WHO guidelines were screened for 24-h ambulatory blood pressure measurement. Eighty-five (66.4%) presented a 24-h mean blood pressure > 135/85 mmHg. All 85 patients were screened for M-mode, B-mode echocardiography, PW Doppler and 24-h ECG Holter recordings. RESULTS: Sixty patients (70.6%) were affected by left ventricular hypertrophy and 25 were free (29.4%). Thirty-six patients (42.4%) had left ventricular diastolic dysfunction, 49 were free (57.6%). According to Lown and Wolf's classification of ventricular arrhythmia, 20 patients (23.5%) presented Grade I arrhythmia, 5 (5.9%) presented Grade II, 4 (4.7%) Grade III, 9 (10.6%) Grade IVA, 20 (23.5%) Grade IVB, 12 (14.1%) Grade V and 15 patients (17.6%) were free from premature ventricular complexes, namely Grade 0 arrhythmia. Left ventricular hypertrophy was found to correlate significantly with the arrhythmia score, r = 0.552 for p < 0.0001. Moreover, left ventricular diastolic dysfunction correlated significantly with the arrhythmia score, r = 0.495 for p < 0.0001. There was also a good correlation between left ventricular hypertrophy and left ventricular diastolic dysfunction, r = 0.616 for p < 0.0001. Among patients affected by left ventricular diastolic dysfunction and left ventricular hypertrophy, the correlation with the arrhythmia score was even closer, r = 0.586 for p < 0.0007. CONCLUSIONS: We conclude that by using a more selective criterion for the diagnosis of hypertension, we can identify patients with a highly significant statistical correlation between left ventricular hypertrophy and ventricular arrhythmia score, and also between diastolic dysfunction and the ventricular arrhythmia score, due to a more severe stage of disease. It is useful to detect those patients affected by ventricular arrhythmias for the primary prevention of major cardiovascular events.

Adult↗
PubMed1998

Intrarenal arteriosclerosis and impairment of kidney function in NIDDM subjects.

It is currently under debate whether the pathogenesis of end-stage renal failure in non-insulin-dependent diabetes mellitus (NIDDM) is a consequence of microangiopathy alone. The aim of this study was to investigate intrarenal arteriosclerosis and its correlation with kidney function in NIDDM. In 36 diabetic subjects, and in 10 age- and sex-matched healthy control subjects we measured kidney volume and resistive index of the interlobar arteries by duplex Doppler ultrasonography. Clinical and metabolic parameters, renal function and vascular sequelae of the disease were also evaluated. In diabetic subjects resistive index (median 0.72, range 0.54-0.79) was higher than in control subjects (median 0.62, range 0.57-0.66) (2p < 0.002). Kidney volume and resistive index correlated with age (p < 0.004), body mass index (p < 0.001), mean blood pressure (p < 0.001), total and LDL cholesterol (p < 0.01) and creatinine clearance (p < 0.001 and < 0.01, respectively). Kidney volume also correlated with HbA1 (p < 0.01) and resistive index with uric acid (p < 0.01). Lower body macroangiopathy was associated with increased resistive index and reduced kidney volume (2p < 0.05), while upper body macroangiopathy and microangiopathy were not. Our data suggest that macroangiopathy rather than microangiopathy is mainly responsible for impairment of kidney function in NIDDM. The resistive index of interlobar arteries seems to be a reliable marker of intrarenal arteriosclerosis and can be used as a non-invasive, easily available parameter of its evolution.

Arteriosclerosis↗
PubMed1998

Basal synthesis of heat shock protein 70 increases with age in rat kidneys.

The heat shock protein (HSP) system is a mechanism of cell defense induced by stress, constitutively expressed during basal conditions and essential to the maintenance of cellular integrity. Acutely induced HSP synthesis decreases with aging, but the effect of age on the basal expression of HSP70 has not been specifically addressed so far. The aim of this work is to study the age-dependent basal concentrations of HSP70 mRNA in rat kidneys. In 8 young (2-3 months), 6 adult (6-11 months) and 6 old male Wistar rats (22-27 months), steady-state concentrations of HSP70 and gamma-actin mRNA and of rRNA were measured. Pentosidine was measured by HPLC. The basal, unstimulated HSP70 mRNA is increased in young and old rats compared with adult subjects [young: 182% of adult levels (100-299), old: 167% of adults (142-209); p < 0.005]. The amount of pentosidine increases with age (young: 0.6 +/- 0.1; adult: 1.65 +/- 0.15; old: 2.3 +/- 0.3 pmol/mg of protein; p < 0.0001). It seems likely that different mechanisms are responsible for the increased HSP70 basal synthesis in both the young and old animals. The prevalence of anabolic activity can trigger the increased basal production of HSP70 in young rats. The accumulation of posttranslational modified proteins, documented by pentosidine, can chronically enhance HSP70 synthesis in aged animals. The suppression of the synthesis of other proteins accompanying HSP-selective production might contribute to the impairment of specific cell functions in aging.

Actins↗
PubMed1998

Removal of tumours of the orbital apex via a postero-lateral orbitotomy.

BACKGROUND: The surgical management of pure apical tumours of the orbit may be problematic with traditional approaches. A postero-lateral approach, specifically designed for apical growths, provides a more favourable angle of vision through a relatively small bone opening. METHODS: A series of 103 consecutive cases of intraorbital tumours, operated on in a community-based institution, was retrospectively reviewed. Out of this series, 8 patients, harbouring lesions located in the posterior intraconal space, underwent a postero-lateral orbitotomy. This approach, through a small opening on the orbital and temporal portions of the greater wing of the sphenoid, with the lesser sphenoidal wing, the orbital plate of the frontal bone, the lateral rim of the orbit being maintained intact, allowed adequate exposure of the orbital apex and successful extirpation of the tumours. In four patients the histological examination disclosed a cavernoma; the other patients had, respectively, a dermoid cyst, a lymphoma, a hemangiopericytoma and a metastatic melanoma. RESULTS: No recurrences were observed in a follow-up period ranging from 1 to 7 years postoperatively (the patient with melanoma died 16 months after operation for systemic complications of her illness). One patient showed transient weakness of lateral rectus muscle due to surgical manipulation, which subsided in few months. CONCLUSIONS: The postero-lateral orbitotomy represents a reliable alternative to other traditional surgical approaches when dealing with tumours of the orbital apex, providing excellent exposure of this region with a low rate of operative morbidity.

Adult↗
PubMed1995

Surgical treatment of fractures of the thoracic and lumbar spine via the transpedicular route.

Sixty-seven consecutive patients with burst or dislocation fractures of the thoracic or lumbar spine were submitted to early surgical reduction, via the transpedicular route, over a 5-year period. The first 22 patients received Harrington instrumentation, while transpedicular devices were applied in the last 44 cases, at either the thoracic or the lumbar level. One patient did not receive any spinal instrumentation. This surgical approach was found to be reliable in achieving a near-anatomical reconstruction of the fractured spinal segment. The rate of post-operative complications was low. Placement of transpedicular devices proved to be a safe and effective procedure. The overall results were consistent with the thesis that the transpedicular approach compares favourably with alternative surgical methods.

Adolescent↗
PubMed1994

Delayed worsening of the surgical correction of angular and axial deformity consequent to burst fractures of the thoracolumbar or lumbar spine.

Forty-one patients with burst fractures of the thoracolumbar junction, or the lumbar spine (T12 to L5), were followed for 6-48 months (mean follow-up = 19.9 months) after early surgery (usually within 24 hours). Preoperative, early postoperative, and late postoperative degrees of kyphosis, as well as percent reduction of the height of the vertebral body were calculated and compared. Early postoperative radiologic evaluations showed a statistically significant difference (p < 0.0001) between the mean values of both parameters calculated respectively before and after surgery. The decrease of the surgical correction, from the initial postoperative radiographs to follow-up, was statistically significant (p < 0.0001). However, the final values were better when compared with the preoperative features (p < 0.003 and p < 0.0001, respectively for degree of kyphosis and reduction in vertebral height.

Adolescent↗
PubMed1994

Increased expression of basement membrane collagen in human diabetic retinopathy.

Basement membrane thickening is the most prominent and characteristic feature of early diabetic microangiopathy. Unknown is not only the causative process but also whether the thickening reflects increased synthesis of specific components. Because collagen type IV is uniquely present in basement membranes and represents their predominant structural element, we studied its expression in retinas obtained postmortem from five patients with 8 +/- 3 yr of diabetes and six nondiabetic controls. The collagen IV transcript proved to be rare in adult human retina and undetectable by Northern analysis. We thus identified a set of primers and conditions to detect the transcript by the reverse transcriptase polymerase chain reaction and to measure its level relative to an endogenous internal standard (beta-actin mRNA). In the diabetic patients the levels of collagen IV mRNA were increased twofold over levels in controls, whereas the actin mRNA levels were similar in the two groups. Hence, the collagen IV/actin ratio was 0.53 +/- 0.15 in diabetic samples and 0.24 +/- 0.09 in control samples (P = 0.004). These results indicate that diabetes induces a twofold increase in the expression of collagen IV by the cells that synthesize basement membranes in the adult retina (vascular cells). Insofar as high ambient glucose in vitro elicits the same effect, it may be proposed that basement membrane thickening in diabetes results from enhanced synthesis of specialized component molecules sustained by hyperglycemia.

Actins↗
PubMed1994

Spinal cord stimulation for the treatment of progressive systemic sclerosis and Raynaud's syndrome.

Progressive Systemic Scleroderma (PSS) is a generalized disease of connective tissue involving the skin, as well as other internal organs. The cutaneous signs are characterized by a progressive sclerosis and loss of function or dexterity in the hands. Between 1987 and 1992, 15 patients affected by scleroderma were treated by means of spinal cord stimulation (SCS) in order to reduce signs and symptoms related to vascular damage. The follow-up ranged from 12 months to 6 years. The study confirms that SCS is an effective therapy in patients with PSS and Raynaud's phenomenon because of its beneficial effects on the Raynaud episodes, ulcers, pain, vascular sclerosis and hand function. This method may have a primary role in the treatment of this chronic disorder because of the high probability of failure of other medical or surgical therapy.

Adult↗
PubMed1993

Transpedicular decompression and stabilization of burst fractures of the lumbar spine.

Twenty-seven consecutive patients with neurological impairment due to burst fractures of the lumbar spine were operated upon, via the postero-lateral route, over a 38-month-period. Transpedicular fixation devices [posterior segmental fixator (PSF) or variable screw placement system (VSP)] were applied in all cases, in order to achieve short-segment fusion of the fractured spinal segment. Return to useful motor power or neurological normality (median follow-up: 18.7 months) occurred in 22 cases (81% of the whole series), with this outcome resulting in all but one of the cases with preoperative incomplete neurological deficit. Postoperative encroachment of the spinal canal, degree of kyphotic deformity, and reduction of the vertebral height showed statistically significant differences compared with the corresponding preoperative values.

Adolescent↗
PubMed1992

Increased expression of tissue plasminogen activator and its inhibitor and reduced fibrinolytic potential of human endothelial cells cultured in elevated glucose.

In diabetic patients, elevated plasma levels of t-PA and PAI-1 accompany impaired fibrinolysis. To identify mechanisms for these abnormalities, we examined whether vascular endothelial cells exposed to high glucose upregulate t-PA and PAI-1 production and whether ambient PA activity is decreased concomitantly. In 17 cultures of human umbilical vein endothelial cells grown to confluency in 30 mM glucose, the t-PA antigen released to the medium in 24 h was (median) 52 ng/10(6) cells (range 10-384) and the PAI-1 antigen was 872 ng/10(6) cells (range 217-2074)--both greater (P less than 0.02) than the amounts released by paired control cultures grown in 5 mM glucose--29 ng/10(6) cells (range 7.5-216) and 461 ng/10(6) cells (range 230-3215), respectively. In the presence of high glucose, the steady-state levels of t-PA and PAI-1 mRNAs were increased correspondingly (median 142 and 183% of control, respectively, P less than 0.05); high glucose per se and hypertonicity contributed to the upregulation in additive fashion. The PA activity of conditioned medium from cultures exposed to high glucose was 0.4 IU/ml (range 0.2-0.6), which was significantly lower (P less than 0.02) than the PA activity of control medium (0.5 IU/ml, range 0.2-0.9). No difference was observed when comparing the PA activities of acidified conditioned media, expected to be depleted of inhibitors. Thus, high glucose coordinately upregulates endothelial t-PA and PAI-1 expression through effects exerted at the pretranslational level and enhanced by even mild degrees of hypertonicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Cells, Cultured↗
PubMed1991

Expression of genes related to the extracellular matrix in human endothelial cells. Differential modulation by elevated glucose concentrations, phorbol esters, and cAMP.

To identify agents and mechanisms responsible for the thickened basement membranes characteristic of diabetic angiopathy we examined the effects of high glucose (30 mM) on the expression of genes related to extracellular matrix composition and turnover and investigated whether the changes induced by high glucose were mimicked and sustained by activation of protein kinase C or A. In human umbilical vein endothelial cells high glucose increased fibronectin, collagen IV, tissue plasminogen activator (tPA), and plasminogen activator-inhibitor 1 (PAI-1) mRNA levels 2-fold but did not affect type IV and interstitial collagenase expression. Acute treatment with phorbol esters resulted in increased collagen IV, tPA, PAI-1, and interstitial collagenase mRNAs; the type IV collagenase mRNA levels were instead suppressed to 50% of control. Upon longer exposure to phorbol esters (48 h) suppression of fibronectin and PAI-1 mRNAs also occurred. Intracellular elevation of cAMP led to over-expression of fibronectin and type IV collagenase and potentiated the effects of phorbol esters on collagen IV, tPA, and interstitial collagenase expression. The mRNA changes induced by high glucose occurred in the absence of protein kinase C activation or cAMP elevation. These studies indicate that events other than activation of protein kinase C or A bridge high ambient glucose to changes in endothelial cell gene expression that may contribute to diabetic angiopathy.

1-Methyl-3-isobutylxanthine↗