Biomedical subjects

Martin Paul

Publications and source records attributed to Martin Paul.

At least 37 records · Page 2Linked to original sources

PubMed2003

Uncoupling protein 1 and 3 polymorphisms are associated with waist-to-hip ratio.

Body weight regulation is a complex phenotype also depending on the action of uncoupling proteins (UCPs) that mediate the "uncoupling" of respiration leading to the dissipation of energy as heat. This study investigated whether genetic variants in the genes encoding UCP-1 and UCP-3 are associated with different obesity-related phenotypes in 162 whites with a wide range of body mass index. All subjects were genotyped for the polymorphisms UCP-1 A-3826G, UCP-1 Ala64Thr, and UCP-3 C-55T using a PCR-based restriction method with appropriate enzymes. The frequencies of the UCP-1 3826G, UCP-1 64Thr, and UCP-3 55T alleles were 27.2%, 12.0%, and 22.8%, respectively. No significant associations were observed between polymorphism and body mass index or obesity. However, after adjustment for gender, age, body mass index, and diabetes mellitus the waist-to-hip ratio was significantly associated with UCP-1 Ala64Thr ( P=0.003) and UCP-3 C-55T ( P=0.02) but not with UCP-1 A-3826G. The higher waist-to-hip ratios associated with the UCP-1 64Thr and UCP-3 55T alleles were due to higher waist circumference in these allele carriers. In conclusion, central obesity in whites as reflected by an increased waist-to-hip ratio is associated with the UCP-1 Ala64Thr and UCP-3 C-55T polymorphisms. To what extent these genotypes contribute to the overall cardiovascular risk remains to be elucidated.

Body Constitution↗

PubMed2003

Transgenic rat model of Huntington's disease.

Huntington's disease (HD) is a late manifesting neurodegenerative disorder in humans caused by an expansion of a CAG trinucleotide repeat of more than 39 units in a gene of unknown function. Several mouse models have been reported which show rapid progression of a phenotype leading to death within 3-5 months (transgenic models) resembling the rare juvenile course of HD (Westphal variant) or which do not present with any symptoms (knock-in mice). Owing to the small size of the brain, mice are not suitable for repetitive in vivo imaging studies. Also, rapid progression of the disease in the transgenic models limits their usefulness for neurotransplantation. We therefore generated a rat model transgenic of HD, which carries a truncated huntingtin cDNA fragment with 51 CAG repeats under control of the native rat huntingtin promoter. This is the first transgenic rat model of a neurodegenerative disorder of the brain. These rats exhibit adult-onset neurological phenotypes with reduced anxiety, cognitive impairments, and slowly progressive motor dysfunction as well as typical histopathological alterations in the form of neuronal nuclear inclusions in the brain. As in HD patients, in vivo imaging demonstrates striatal shrinkage in magnetic resonance images and a reduced brain glucose metabolism in high-resolution fluor-deoxy-glucose positron emission tomography studies. This model allows longitudinal in vivo imaging studies and is therefore ideally suited for the evaluation of novel therapeutic approaches such as neurotransplantation.

Animals↗

PubMed2003

Cardiac fibrosis occurs early and involves endothelin and AT-1 receptors in hypertension due to endogenous angiotensin II.

OBJECTIVES: We investigated if endothelin (ET)-1 and the renin-angiotensin-aldosterone system play a role in cardiac fibrosis. BACKGROUND: Angiotensin II (Ang II) can induce cardiac fibrosis, but the underlying mechanisms are incompletely understood. METHODS: Four-week-old transgenic (mRen2)27 rat (TGRen2) received for four weeks a placebo, the mixed ET(A)/ET(B) endothelin receptor antagonist bosentan, the angiotensin II type I receptor (AT-1) antagonist irbesartan, the ET(A) endothelin receptor antagonist BMS-182874, and a combined treatment with irbesartan plus BMS-182874. We measured collagen density on Sirius red-stained serial sections of the left ventricle (LV) with a photomicroscope equipped with specific software and assessed the gene expression of procollagen alpha1(I), atrial natriuretic peptide (ANP), transforming growth factor-beta 1 (TGFbeta1), endothelin converting enzyme, and ET(B) receptor. RESULTS: In the placebo group, hypertension was associated with LV hypertrophy and cardiac fibrosis (LV weight: 4.0 +/- 0.3 mg/g body weight; collagen density: 2.21 +/- 0.16%), which were all prevented with irbesartan (2.3 +/- 0.1, 1.30 +/- 0.13, p < 0.001), but not with BMS-182874 (4.0 +/- 0.2, 2.41 +/- 0.22). Bosentan also prevented fibrosis (1.39 +/- 0.18) but not hypertension and LV hypertrophy (3.38 +/- 0.27). Combined irbesartan and BMS-182874 treatment prevented LV hypertrophy (2.9 +/- 0.1) but not fibrosis (2.52 +/- 0.16). Collagen density correlated (r = 0.414, p < 0.05) with plasma aldosterone levels. In TGRen2 with LV hypertrophy, the gene expression of ANP and ET(B) but not that of TGFbeta1 and procollagen alpha1(I) was increased. CONCLUSIONS: In Ang II-dependent hypertension, cardiac fibrosis was associated with LV hypertrophy and was hindered by both mixed ET(A)/ET(B) blockade and AT-1 blockade. Only the latter treatment prevented both hypertension and LV hypertrophy. Thus, there is a dissociation between the mechanisms of cardiac fibrosis and hypertension, which do and do not entail ET-1, respectively.

Angiotensin II↗

PubMed2003

Induction of coxsackievirus-adenovirus-receptor expression during myocardial tissue formation and remodeling: identification of a cell-to-cell contact-dependent regulatory mechanism.

BACKGROUND: The coxsackievirus-adenovirus receptor (CAR) was cloned as a receptor for both viruses, but its primary biological functions and regulatory mechanisms are unknown. CAR was low in healthy adult myocardium, whereas strong CAR reexpression was observed in human dilated cardiomyopathy. The molecular mechanisms of CAR induction in cardiomyocytes are unknown. METHODS AND RESULTS: We report on CAR regulation during development, CAR induction after myocardial infarction, and cell-to-cell contact-dependent CAR regulation in the rat. The high CAR expression during development in various organs decreased up to 190-fold after birth. After infarction resulting in severe cardiac dysfunction (dP/dt(max), -53%; dP/dt(min), -58%; left ventricular pressure, -45%), CAR was induced locally in cardiomyocytes of the infarct zone, where it was also expressed by capillary-like CD31+ structures and CD18+ interstitial cells, whereas it remained confined to subendothelial layers of arterioles and venules. In cultured cardiomyocytes, endothelin-1, cardiotrophin-1, leukemia-inhibiting factor, and cyclic stretch had no effect on CAR, whereas at high versus low cell density, CAR was suppressed up to 10-fold (P=0.006). Conditioned media from low- or high-density cardiomyocytes or cardiofibroblasts had no effect. CONCLUSIONS: The locally confined CAR upregulation after infarction makes induction by various humoral factors unlikely, because cardiac dysfunction results in high activities of sympathetic and renin-angiotensin systems and cytokines. The cell culture experiments identify a cell-to-cell contact-dependent mechanism of CAR regulation. Further characterization of the signals linking cell-to-cell interactions to CAR gene expression may provide insight into mechanisms and functional consequences of the generalized CAR induction in dilated cardiomyopathy, and of its local induction after myocardial infarction.

Alternative Splicing↗

PubMed2003

Differential binding of transcription factor E2F-2 to the endothelin-converting enzyme-1b promoter affects blood pressure regulation.

The endothelin-converting enzyme (ECE)-1 gene is a candidate for human blood pressure (BP) regulation and we report the identification of the new gene variants T-839G, C-338A, L75F, A677V and C+295T. Transient transfection of the reporter constructs containing the -338A allele showed an increase in promoter activity compared with the wild-type promoter. EMSA revealed the specific binding of E2F-2 to both ECE-1b promoter sequences, with the -338A allele being associated with an increased affinity to E2F-2 compared with -338C. The clinical relevance of this finding was analyzed in 704 hypertensive patients. In untreated hypertensive women, both the -338A and -839G alleles were significantly associated with ambulatory BP values. This study provides the first evidence of a link between the cell-cycle-associated E2F family and BP regulation via a component of the endothelin system.

Adult↗

PubMed2003

ERK1/2-dependent contractile protein expression in vascular smooth muscle cells.

In vivo, vascular smooth muscle (VSM) cells change their contractile phenotype toward a more proliferative phenotype during the pathogenesis of vascular diseases. Because these dedifferentiated VSM cells may gradually regain contractile functions, we aimed to identify signaling pathways that result in an increased expression of contractile proteins in VSM cells. In vitro, serum and thrombin induced a reversible upregulation of smooth muscle myosin heavy-chain (SM-MHC) in cultured neonatal rat VSM cells. Cotransfection of a SM-MHC-promoter chloramphenicol acetyltransferase-construct with dominant-negative N17Ras or N17Raf or treatment with the mitogen-activated/ERK-activating kinase (MEK) inhibitor PD 98059 concentration dependently decreased the serum- or thrombin-induced SM-MHC promoter activity. Consistently, the serum- or thrombin-induced phosphorylation of MEK and extracellular signal-regulated kinase 1/2 (ERK1/2) coincided with a MEK-dependent nuclear accumulation of phosphorylated ERK1/2 and subsequent nuclear phosphorylation of the transcription factors c-myc and Elk-1. A 5'-deletion analysis of cis-elements within the SM-MHC promoter demonstrated that a conserved region (nucleotide -1346 to -1102) was required for both cell type-specific expression and serum- or thrombin-induced upregulation of the SM-MHC promoter in VSM cells. Within this region, 2 CArG-boxes, a GC-rich element, and a CTF/NF-1 site are critical positively acting cis-elements for the serum- or thrombin-induced upregulation of SM-MHC. We conclude that the serum- or thrombin-induced differentiation requires an intact Ras/Raf/MEK/ERK signaling cascade, nuclear translocation of activated ERK1/2, phosphorylation of transcription factors, and several cis-elements within the SM-MHC promoter.

Animals↗

PubMed2003

The isolated normothermic hemoperfused porcine forelimb as a test system for transdermal absorption studies.

For transdermal absorption studies, a porcine skin model that maintains the characteristics of the skin as close to physiological conditions as possible should be established because of the close similarity of porcine and human skin. Perfusion flow, glucose concentration, and oxygen supply were varied and organ resistance and lactate concentration were measured as parameters for organ performance. Transdermal absorption studies were performed using nitroglycerin or estradiol as test solutes. By the use of a standardized perfusion apparatus, limbs were perfused with a normothermic blood/electrolyte mix over a 6-h period. Organ resistance and lactate concentration were lower in limbs perfused with high flow as compared to perfusion with low flow. However, high perfusion flow caused an initial increase of hemolysis in the venous perfusate resulting in a higher concentration of free hemoglobin compared to low perfusion flow conditions. Glucose level in the perfusate was maintained within the porcine physiological range. By applying optimized conditions, the transdermal absorption of nitroglycerin or estradiol released from transdermal therapeutic systems was investigated. A time-dependent accumulation of the substances in the perfusion medium was observed, indicating the continuous uptake via the skin. After 6 h (nitroglycerin) or 5 h (estradiol) of perfusion, test substances accumulated to concentrations comparable to those described in humans. In conclusion the perfused porcine limb may serve as a reliable test system for transdermal absorption studies. The model is suited to the replacement of animal testing and has a higher predictive potential because of the similarities of porcine and human skin.

Animals↗

PubMed2003

Functional effects of acute coronary occlusion and catecholinergic stimuli on the isolated normothermic hemoperfused porcine heart.

The aim of this study was to characterize functional parameters in the isolated and normothermic hemoperfused porcine beating heart model after pathophysiological stimuli for extended perfusion periods. Hearts were prepared and connected to a specially developed perfusion equipment, which simultaneously allowed perfusion with warm autologous blood as well as blood dialysis. Two groups were established: group A (12 hearts: no intervention) and group B (6 hearts: occlusion of the ramus circumflexus of the left coronary artery for 2 hours). Blood gas analyses and oxymetry were performed at baseline and every 30 min during a 6 hours perfusion period. Coronary perfusion pressure (CPP) and blood flow (CBF), right and left ventricular pressure, blood and dialyzate pH-values, and temperature were monitored online by a microcontroller. A steady state regarding the CPP and the CBF was achieved after 1 hour of perfusion for both groups. In group B, CPP increased during occlusion. Comparison of both groups showed no significant differences in the bicarbonate and sodium levels in blood and dialyzate. The potassium concentration in blood and dialyzate increased in both groups constantly during the experiments. No clear alteration of the oxygen consumption was observed. Lactate levels in blood and dialyzate increased during occlusion as did the aspartataminotransferase (AST) venous levels (both determined only for group B). Four concentrations of norepinephrine were injected into the stem of the coronary arteries (10, 20, 40, 80 microg). A clear inotropic effect of this hormone on right and left ventricular pressure was observed. It was concluded that longer perfusion periods and simulation of myocardial infarction for a clinically relevant period can be performed using this model. In addition, right and left ventricular function appear to be well preserved in this model, since the isolated porcine heart responded to norepinephrine stimuli.

Acute Disease↗

PubMed2003

Differential regulation of in vivo angiogenesis by angiotensin II receptors.

Angiotensin II (ANG II), a key regulator of blood pressure and body fluid homeostasis, exerts mitogenic effects on endothelial cells. We therefore hypothesized that ANG II could be a mediator between homeostatic changes within the vascular perfusion bed and growth factor-driven angiogenesis. In the present study, we applied the alginate implant angiogenesis model in mice with normal ANG II levels, elevated ANG II levels by transgenic overexpression of angiotensinogen (AOGEN), or in AT2 receptor-deficient mice. We demonstrate that a decrease in the amount of circulating ANG II by the angiotensin-converting enzyme (ACE) inhibitor enalapril or the AT1 receptor antagonist losartan induced a stimulation of in vivo angiogenesis implying an inhibitory function of ANG II through the AT1 receptor. However, the strong increase of angiogenesis in AOGEN-transgenic mice compared with mice with normal ANG II levels suggests additional stimulatory activity. We showed that the ANG II-induced stimulation of angiogenesis is linked to the AT2 receptor as an impaired induction of angiogenesis was obtained in AT2 receptor knockout mice. These findings provide the first evidence that the AT2 receptor mediates a stimulation of in vivo angiogenesis and indicate that ANG II is a humoral regulator of peripheral angiogenesis involving two receptor subtypes with opposing actions.

Alginates↗

PubMed2003

Regulation of the major isoform of human endothelin-converting enzyme-1 by a strong housekeeping promoter modulated by polymorphic microsatellites.

BACKGROUND: Human endothelin-converting enzyme (ECE)-1, the key enzyme in endothelin biosynthesis, shows broad cell and tissue expression within the cardiovascular system. Expression of ECE-1c, which represents the major ECE-1 isoform, is directed by an alternative promoter, but the mechanisms of ECE-1c promoter regulation are largely unknown. As ECE-1c transcription is initiated from several start sites, we hypothesized that the ECE-1c promoter functions as a housekeeping promoter. OBJECTIVE: To investigate the putative housekeeping function of the ECE-1c promoter in vascular endothelial cells, which represent a main site of its expression. RESULTS: Using promoter reporter assays, gel shift and supershift assays, we have demonstrated, in human endothelial EA.hy926 cells, functionality of cis-acting elements for binding of the CAAT-box binding protein NF-YB, GATA-2) E2F-2, and a GC-box binding factor, which are spatially associated with transcriptional start sites of ECE-1c. In the more upstream promoter region we have identified three highly polymorphic dinucleotide repeats, 5'-(CA)n, (CG)n and 3'-(CA)n, which strongly affected promoter function in endothelial EA.hy926 cells (2.7-fold activation comparing the most active to the least active allele) and, in a similar manner, in human neuronal KELLY cells. Finally, by in-vitro methylation, we were able to achieve strong suppression of the ECE-1c promoter activity in endothelial cells. CONCLUSION: Our results provide a molecular explanation for constitutive expression of ECE-1c mRNA. Modulation by genetic and epigenetic mechanisms as revealed in our study may account for interindividual variation of the constitutive endothelin system activity in humans and thus influence individual predisposition to cardiovascular disease.

Aspartic Acid Endopeptidases↗

PubMed2003

Renal damage is not improved by blockade of endothelin receptors in primary renin-dependent hypertension.

OBJECTIVE: Secondary activation of the renin-angiotensin system plays a major role in the progression of chronic nephropathies, and blockade of endothelin (ET) receptors has been shown to confer nephroprotection in experimental models of proteinuric renal disease. We tested the nephroprotective potential of selective endothelin A receptor (ETA) and non-selective ETA and endothelin B (ETA/B) receptor blockade in the TGR(mRen2)27 transgenic rat model with renin-dependent hypertension (Ren2). DESIGN: Ren2 animals were treated between 10 and 30 weeks of age with the selective ETA receptor antagonist darusentan (Ren2-ETA) and the ETA/B receptor antagonist Lu420627 (Ren2-ETA/B), and compared with transgene negative Sprague-Dawley (SD) controls. Since the elevated systolic blood pressure in Ren2 was not affected in either Ren2-ETA or Ren2-ETA/ETB, an additional Ren-2 group was treated with a non-antihypertensive dose of the angiotensin II type 1 receptor blocker eprosartan (Ren2-AT1). RESULTS: During the 20-week observation period 35% of untreated Ren2, 30% of Ren2-ETA/B, 50% of Ren2-ETA, and 83% of Ren2-AT1 animals survived compared with 100% of SD rats. Renal endothelin-1 mRNA expression and proteinuria (4.1-fold) were significantly elevated in Ren2 compared with SD rats (P < 0.05, respectively). Proteinuria was normalized to SD control levels in Ren2-AT1 (P < 0.05) but increased further in Ren2-ETA (7.7-fold) and Ren2-ETA/B (15-fold) (P < 0.05, respectively). Glomerulosclerosis, tubulointerstitial damage and renal osteopontin mRNA expression were reduced in Ren2-AT1 (P < 0.05, respectively) but remained unchanged or increased further in Ren2-ETA and Ren2-ETA/B compared with Ren2. CONCLUSION: ET receptor blockade fails to improve renal damage and mortality in primary renin-dependent hypertension.

Acrylates↗

PubMed2003

Digoxin-like immunoreactive substance in nonoliguric hyperkalemia of the premature infant.

Nonoliguric hyperkalemia of premature infants probably results from a transient inhibition of membrane-bound Na+/K+-ATPase during the first 24 h after birth. We hypothesized that the endogenous digitalis-like activity of the serum of premature infants, which inhibits the Na+/K+-ATPase, triggered hyperkalemia. Serum concentrations of potassium ([K+]) and of the digoxin-like immunoreactive substance ([DLIS]) were measured during the first 24 h after birth in 60 infants including 30 infants <30 gestational weeks. Contrary to our hypothesis, there was a negative linear correlation between [DLIS] at birth and [K+] 24 h after birth (r2 = 0.24, p < 0.002). 24 h after birth there was no correlation between [DLIS] and [K+]. Thus, a major role of DLIS in nonoliguric hyperkalemia could not be established.

Cardenolides↗

PubMed2003

Weightlessness induced apoptosis in normal thyroid cells and papillary thyroid carcinoma cells via extrinsic and intrinsic pathways.

Apoptosis plays a pivotal role in development, tissue homeostasis, cancer, immune defense, and response to weightlessness. It can be initiated by external signals via death receptors, but may also emerge from mitochondria. We exposed mitochondria-rich thyroid carcinoma cells (ONCO-DG1 cell line) and normal thyroid cells (HTU-5) to conditions of simulated microgravity. After 24 h, 10% of the cancer cells had entered a Fas-dependent apoptotic pathway, but destruction and redistribution of mitochondria, microtubuli disruption, and caspase-3 activation were also detected, demonstrating the activation of extrinsic as well as intrinsic pathways. Furthermore, ONCO-DG1 cells grown on the clinostat showed elevated amounts of Bax, but reduced quantities of bcl-2. In addition, signs of apoptosis became detectable, as assessed by terminal deoxynucleotidyl transferase-mediated dUTP digoxigenin nick end labeling, 4',6-diamidino-2-phenylindole staining, and 85-kDa apoptosis-related cleavage fragments. These fragments resulted from enhanced 116-kDa poly(ADP-ribose)polymerase activity and apoptosis. Apoptosis was also detected in normal HTU-5 cells, as demonstrated by electron microscopy, activation of caspase-3, increases in Fas and Bax, and elevation of 85-kDa apoptosis-related cleavage fragments resulting from enhanced poly(ADP-ribose) polymerase activity. Gravitational unloading affects the mitochondria and thereby may trigger apoptosis in thyroid cells subjected to weightlessness by clinorotation.

Apoptosis↗

PubMed2002

Nitric oxide in the human hair follicle: constitutive and dihydrotestosterone-induced nitric oxide synthase expression and NO production in dermal papilla cells.

The free radical nitric oxide, generated by different types of epidermal and dermal cells, has been identified as an important mediator in various physiological and pathophysiological processes of the skin, such as regulation of blood flow, melanogenesis, wound healing, and hyperproliferative skin diseases. However, little is known about the role of NO in the human hair follicle and in hair cycling processes. Here we demonstrate for the first time that dermal papilla cells derived from human hair follicles spontaneously produce NO by measuring nitrate and nitrite levels in culture supernatants. This biomolecule is apparently formed by the endothelial isoform of nitric oxide synthase, which was detected at the mRNA and protein levels. Remarkably, basal NO level was enhanced threefold by stimulating dermal papilla cells with 5alpha-dihydrotestosterone (DHT) but not with testosterone. Addition of N-[3-(aminomethyl)benzyl]acetamidine (1400W), a highly selective inhibitor of inducible nitric oxide synthase, restrained the elevation in NO level induced by DHT. Analyses of DHT-stimulated cells at the mRNA and protein levels confirmed the expression of inducible nitric oxide synthase. These findings suggest NO as a signaling molecule in human dermal papilla cells and implicate basal and androgen-mediated NO production to be involved in the regulation of hair follicle activity.

Adult↗

PubMed2002

Expression of endothelins in human cardiogenesis.

Genetic disruption of endothelin (ET) 1, endothelin-converting enzyme (ECE) 1, and endothelin receptor A (ET(A)) in "knockout" or mutant mouse models result in defects in branchial arch derived craniofacial tissues and in cardiac outflow and great vessel structures. Interestingly, certain types of human congenital cardiovascular malformations such as Catch 22 syndrome and type B interruption of the aortic arch strongly resemble defects seen in knockout animal models. To better address the exact involvement of the ET system in heart formation we explored the spatiotemporal pattern of expression of the components of the ET system during critical phases of cardiogenesis in the human embryo (3-6 weeks of development; Carnegie stages 10-17) by in situ hybridization. We detected high ET-1 mRNA expression in endocardial cells lining the heart outflow tract in the region where the future aortic valves will form. No hybridization signal corresponding to pre-pro-ET-3 was observed in the heart. At the same location, the underlying myocytes express ET(A) mRNA. Whereas a functional role of ET in the valve formation can be proposed because of the simultaneous presence of all the components of the endothelin system (ET-1/ECE-1/ET(A)), this seems not to be the case for the formation of the ventricular septum where endocardial cells do not express ET-1, and only a weak ET(A) hybridization signal was detected in the surrounding myocardium. An abnormal hemodynamism indirectly due to valve malformation may be the indirect cause of this septal defect. The results of this study suggest an important role for the ET system in the formation of certain anatomical structures of the developing human heart.

Aorta, Thoracic↗

PubMed2002

Transgenic overexpression of the sarcoplasmic reticulum Ca2+ATPase improves reticular Ca2+ handling in normal and diabetic rat hearts.

Slowed relaxation in diabetic cardiomyopathy (CM) is partially related to diminished expression of the sarcoplasmic reticulum (SR) Ca2+-ATPase SERCA2a. To evaluate the impact of SERCA2a overexpression on SR Ca2+ handling in diabetic CM, we 1) generated transgenic rats harboring a human cytomegalovirus enhancer/chicken beta-actin promotor-controlled rat SERCA2 transgene (SERCA2-TGR), 2) characterized their SR phenotype, and 3) examined whether transgene expression may rescue SR Ca2+ transport in streptozotocin-induced diabetes. The transgene was expressed in all heart chambers. Compared to wild-type (WT) rats, a heterozygous line exhibited increased SERCA2 mRNA (1.5-fold), SERCA2 protein (+26%) and SR Ca2+ uptake (+37%). Phospholamban expression was not altered. In SERCA2-TGR, contraction amplitude (+48%) and rates of contraction (+34%) and relaxation (+35%) of isolated papillary muscles (PM) were increased (P2+ uptake and SERCA2 protein of SERCA2-TGR were 1.3-fold higher (P2+ uptake, accelerates relaxation and compensates, in part, for depressed Ca2+ uptake in diabetic CM. Therefore, SERCA2 expression might constitute an important therapeutic target to rescue cardiac SR Ca2+ handling in diabetes.

Animals↗

PubMed2002

Low doses of 2,3,7,8-tetrachlorodibenzo- p-dioxin increase transforming growth factor beta and cause myocardial fibrosis in marmosets ( Callithrix jacchus).

Epidemiological studies have suggested an association between exposure to dioxins and cardiovascular morbidity and mortality. However, cardiotoxic effects of low doses of 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) in animals have not been reported so far. We studied the hearts of male marmosets ( Callithrix jacchus)after treatment with single subcutaneous doses of 1, 10 or 100 ng TCDD/kg body weight or vehicle (toluene/DMSO 1+2 v/v, 100 microl/kg body weight). The animals were killed 2 or 4 weeks after treatment. Tissue samples of left ventricular myocardium were stained with picrosirius red and examined histologically along with quantitative image analysis. Extracellular matrix proteins were additionally analysed by western blotting. Monkeys showed no overt signs of toxicity nor did their relative heart weights differ significantly depending on treatment. Histology revealed an increase of picrosirius red-positive area above control values in 2 of 4 (1 ng TCDD/kg body weight), 6 of 12 (10 ng/kg) and 6 of 10 (100 ng/kg) marmosets. Western blotting confirmed these histological findings showing an increase of collagen, fibronectin and laminin in the hearts of TCDD-treated animals. Western blotting additionally showed an increased concentration of transforming growth factor beta1 (TGF-beta1) as well as TGF-beta receptor type I which could be a functional link to the effects on extracellular matrix. Our findings might explain the association of TCDD exposure with increased cardiovascular mortality observed in epidemiological studies and should stimulate further research on the role of changes in the extracellular matrix in the toxic effects of dioxins and related substances on other organs.

Animals↗

PubMed2002

Studying genotype-phenotype relationships: cardiovascular disease as an example.

Cardiovascular disease is a multifactorial disorder resulting from the complex interaction of a plethora of both environmental and genetic factors. The "candidate gene" approach aims at identifying the genes contributing to cardiovascular disease assessing their entire polymorphic spectrum and the consequences of their combination in appropriate large association studies. In view of the sequence data available for the entire human genome, candidate sequences will more easily be traced and located in their chromosomal context. More powerful sequencing devices are available and will hopefully give reliable and reproducible data not only on the nucleotide sequence diversity in different populations throughout candidate regions of the human genome. The choice and the assessment of disease-related or intermediate phenotypes, especially in clinical settings, will be again more crucial in the future when the knowledge of gene sequence variation significantly increases. Identification of relevant genes and genetic variants involved in the different pathophysiological steps leading to cardiovascular disease may considerably improve our understanding of the mechanisms of the disease course. This may help to identify high-risk individuals and groups or subgroups in whom specific therapeutic interventions are indicated or necessary, leading to an individually adapted clinical management.

Cardiovascular Diseases↗