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Biomedical subjects

Helmut Drexler

Publications and source records attributed to Helmut Drexler.

At least 55 records · Page 3Linked to original sources
PubMed2005

Haematopoietic stem cells improve cardiac function after infarction without permanent cardiac engraftment.

BACKGROUND: Transplantation of bone marrow derived adult stem cells (BMC) improves cardiac function after acute myocardial infarction (MI). However, the cell population mediating myocardial recovery and the fate of the transplanted cells are still controversial. AIMS: We determined the effects of Sca-1+ c-kit+ lin- haematopoietic BMC on cardiac function after MI and the cell fate after transplantation. METHODS: Sca-1+ c-kit+ lin- BMC of male donor C57BL/6 mice were transplanted by intravenous injection into syngenic females after permanent MI. LV dimensions and function were determined by echocardiography and cardiac magnetic resonance imaging, transplanted BMC were identified by Y chromosome DNA in situ hybridization. RESULTS: BMC treatment completely prevented LV dilation (LV end-diastolic volume BMC 70 +/- 16 microl vs. control 122 +/- 41 microl; p < 0.05) and improved fractional shortening (BMC 22.9 +/- 8% vs. control 15.4 +/- 8.4%; p < 0.05) and ejection fraction BMC 68.2 +/- 6.6% vs. control 52 +/- 14.3%; p < 0.05) as early as 3 days after transplantation, but did not decrease infarct size (BMC 27 +/- 6% vs. control 28 +/- 7%, p = n.s.). After 4 weeks, only sporadic cells of male origin were identified in infarcted hearts (< 0.01% of periinfarct cells). CONCLUSION: Intravenous injection of Sca-1+ c-kit+ lin- in BMC after MI improves LV dimensions and function without evidence for long term engraftment.

Animals↗
PubMed2005

STAT3-mediated activation of myocardial capillary growth.

Proper perfusion and vessel integrity are key requisites for myocardial homeostasis. In this regard, myocardial angiogenesis occurs in physiologic and pathologic conditions. Failure in this process and the resulting deficient oxygen supply induce loss and degeneration of cardiomyocytes, atrophy, and interstitial fibrosis and are viewed as a primary cause of myocardial dysfunction and heart failure. In this review, signal transducer and activator of transcription 3 (STAT3) is highlighted as a regulator of proangiogenic circuits promoting vessel formation in the adult heart under physiologic and pathophysiologic conditions. Specifically, STAT3 regulates proangiogenic vascular endothelial growth factor (VEGF) expression and activity in the postnatal heart and suppresses an antiangiogenic and profibrotic gene program by controlling autocrine and paracrine circuits. In addition, signaling through STAT3 represents a necessary survival pathway for cardiomyocytes and endothelial cells and seems to promote cytokine-mediated cardiac angiogenesis. In contrast, STAT3 seems not to be required for differentiation processes of embryonic or adult endothelial progenitor cells. In summary, the properly timed expression and activation of STAT3 play a critical role on cardiac angiogenesis and involve the subtle control of paracrine and autocrine mechanisms regulating angiogenic circuits and survival pathways of cardiomyocytes and endothelial cells.

Animals↗
PubMed2005

Chronic heart failure: an overview of conventional treatment versus novel approaches.

Chronic heart failure (CHF) is a leading cause of hospitalization and is associated with a poor prognosis, although in the past decade substantial progress has been made in understanding the pathophysiology and therapy of CHF with reduced left ventricular (LV) ejection fraction. Use of angiotensin-converting-enzyme inhibitors and angiotensin-receptor antagonists either individually or in combination, certain beta-receptor blockers, and judicious use of aldosterone antagonists, has reduced hospital admission rates and mortality from CHF with reduced LV ejection fraction. More clinical trials are needed, however, particularly in patients with CHF and preserved LV ejection fraction. In patients who remain symptomatic despite medical therapy, and who have long QRS intervals (>0.12 s) and markedly reduced LV ejection fraction, the value of cardiac resynchronization therapy with a biventricular pacemaker has now been demonstrated. Yet, morbidity and mortality remain high, indicating a major need for further improvement. Novel therapies include medical management with statins, vasopressin antagonists, erythropoietin, oxypurinol and levosimendan, which improve vascular and myocardial function and reduce fluid overload, in addition to surgical approaches, which reduce LV remodeling. These routes might not, however, suffice in patients with CHF and LV dysfunction. Prevention of apoptosis and particularly regeneration of cardiac muscle would represent a shift of the current paradigm. Stem-cell-based therapies are rapidly evolving, and while basic science is needed to optimize these strategies, medium-sized clinical studies could help to verify the beneficial effects on LV function. In this review, we discuss current treatment methods and new strategies to improve treatment of CHF.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2005

The clinical significance of endothelial dysfunction.

PURPOSE OF REVIEW: Endothelial dysfunction is thought to play a pivotal role in the development, progression, and clinical complications of atherosclerosis. Several recent studies have addressed the clinical implications of endothelial dysfunction for cardiovascular events, atherosclerosis, restenosis, and heart failure. Novel findings with respect to endothelial progenitor cells and their alteration by cardiovascular risk factors are characterized and potential therapeutic interventions to improve endothelial and endothelial progenitor cell function are discussed. RECENT FINDINGS: Over the past 5 years evidence has accumulated from clinical studies for a close association of the degree of endothelial dysfunction and clinical cardiovascular events in patients with cardiovascular risk factors, coronary disease, acute coronary syndrome, or heart failure. Understanding of the mechanisms leading to endothelial dysfunction has improved, including the notion that dysfunctional endothelial nitric oxide synthase, in part due to deficiency of the endothelial nitric oxide synthase cofactor tetrahydrobiopterin, likely plays an important role. Major progress has been made in understanding the role of endothelial progenitor cells, which likely contribute to both ischemia-induced neovascularization and endothelial regeneration after injury. Endothelial progenitor cell function is altered in patients with cardiovascular risk factors. SUMMARY: Recent research on endothelial and endothelial progenitor cell dysfunction supports their clinical significance and has led to important insights in the pathophysiology of cardiovascular disease and at the same time provides an important opportunity to develop novel therapeutic approaches. Endothelial function represents a valuable surrogate endpoint to assess the impact of therapeutic interventions.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2005

Effects of anesthesia on diastolic function in mice assessed by echocardiography.

BACKGROUND: Transthoracic echocardiography is the predominant diagnostic tool to evaluate systolic and diastolic cardiac function noninvasively in mice. It is known that systolic function is substantially influenced by anesthetic agents used for sedation during echocardiography. However, the effect on diastolic function has not been investigated yet. The following study was conducted to evaluate the influence of different agents on diastolic left ventricular function in mice. METHODS AND RESULTS: The effect of ketamine/xylazine (K/X), ketamine/midazolam (K/M), and tribromoethanol (TBE, Avertin) on diastolic function was measured 5, 15, and 25 minutes after the onset of anesthesia. Ratio of peak early-to-late myocardial diastolic velocities (Ea/Aa; determined by tissue Doppler imaging; TDI), ratio of peak transmitral early (E)- and late-diastolic velocity (E/A), deceleration time (DT), and isovolumic relaxation time (IVRT) correlated significantly with heart rate (HR). Overall, increasing HR contributed to a decrease of E/A-, Ea/Aa ratio, IVRT, and DT, whereas agents characterized by the strongest variation of HR (K/M and TBE) were associated with the greatest effect on diastolic function. CONCLUSION: Left ventricular diastolic function in mice, determined by echocardiography, is dependent on anesthetic agent and timing of measurements after onset of anesthesia.

Anesthetics↗
PubMed2004

Impact of interleukin-6 on plaque development and morphology in experimental atherosclerosis.

BACKGROUND: Vascular lipid accumulation and inflammation are hallmarks of atherosclerosis and perpetuate atherosclerotic plaque development. Mediators of inflammation, ie, interleukin (IL)-6, are elevated in patients with acute coronary syndromes and may contribute to the exacerbation of atherosclerosis. METHODS AND RESULTS: To assess the role of IL-6 in atherosclerosis, ApoE-/--IL-6-/- double-knockout mice were generated, fed a normal chow diet, and housed for 53+/-4 weeks. Mortality and blood pressure were unaltered. However, serum cholesterol levels and subsequent atherosclerotic lesion formation (oil red O stain) were significantly increased in ApoE-/--IL-6-/- mice compared with ApoE-/-, wild-type (WT), and IL-6-/- mice. Plaques of ApoE-/--IL-6-/- mice showed significantly reduced transcript and protein levels of matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, collagen I and V, and lysyl oxidase (by reverse transcriptase-polymerase chain reaction and immunohistochemistry). Recruitment of macrophages and leukocytes (Mac3- and CD45-positive staining) into the atherosclerotic lesion was significantly reduced in ApoE-/--IL-6-/- mice. The transcript and serum protein (ELISA) levels of IL-10 were significantly reduced. CONCLUSIONS: Thus, a lifetime IL-6 deficiency enhances atherosclerotic plaque formation in ApoEK-/--IL-6-/- mice and leads to maladaptive vascular developmental processes. These observations are consistent with the notion that baseline levels of IL-6 are required to modulate lipid homeostasis, vascular remodeling, and plaque inflammation in atherosclerosis.

Animals↗
PubMed2004

Stretch-inducible expression of the angiogenic factor CCN1 in vascular smooth muscle cells is mediated by Egr-1.

CCN1 is an angiogenic factor that promotes cell adhesion, proliferation, and differentiation. CCN1-deficient mice suffer embryonic death because of vascular defects, demonstrating that CCN1 is required for vessel development. Because mechanical stretch may act as a trigger for vessel development, we investigated the impact of mechanical stretch on the regulatory mechanism of CCN1 expression. Mechanical stretch rapidly enhances CCN1 expression and release in vascular smooth muscle cells (VSMC) in vitro and CCN1 expression in murine aortic segments in vivo. Transfection experiments of VSMC with deletion constructs of the CCN1 promoter revealed the regulatory region responsible for the stretch-induced CCN1 expression in the approximately 200-bp promoter region upstream of the TATA-box containing potential binding sites for early growth response-1 (Egr-1), nuclear factor of activated T-cells and cAMP response element binding protein. Decoy oligonucleotides to Egr-1, but not to nuclear factor of activated T-cells or cAMP response element binding protein, abolished the stretch-induced transcription of CCN1. In addition, mutagenesis of the Egr-1 binding site within the CCN1 promoter completely blunted the stretch-induced activation of the promoter. Furthermore, mechanical stretch induced the expression and DNA-binding activity of Egr-1 in VSMC as demonstrated by Western blot and electromobility shift assay. Moreover, a pressure overload-dependent de novo synthesis of Egr-1 was observed after aortic banding. These findings indicate that mechanical stretch leads to enhanced expression of CCN1 via the mechanosensitive transcription factor Egr-1, suggesting a central role for mechanical stretch in the regulation of CCN1-dependent pro-angiogenic potency.

Animals↗
PubMed2004

Statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular function, and survival after experimental myocardial infarction requires endothelial nitric oxide synthase.

BACKGROUND: Endothelial nitric oxide (eNO) bioavailability is severely reduced after myocardial infarction (MI) and in heart failure. Statins enhance eNO availability by both increasing eNO production and reducing NO inactivation. We therefore studied the effect of statin treatment on eNO availability after MI and tested its role for endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular (LV) dysfunction, remodeling, and survival after MI. METHODS AND RESULTS: Wild-type (WT) and eNO synthase (eNOS)-/- mice with extensive anterior MI were randomized to treatment with vehicle (V) or atorvastatin (Ator, 50 mg/kg QD by gavage) for 4 weeks starting on day 1 after MI. Ator markedly improved endothelium-dependent, NO-mediated vasorelaxation; mobilization of endothelial progenitor cells; and myocardial neovascularization of the infarct border in WT mice after MI while having no effect in eNOS-/- mice. LV dysfunction and interstitial fibrosis were markedly attenuated by Ator in WT mice, whereas no effect was observed in eNOS-/- mice after MI. Importantly, Ator significantly increased the survival rate during 4 weeks after MI in WT mice (Ator versus V, 80% versus 46%; P<0.01, n=75) but not in eNOS-/- mice (43% versus 48%; NS, n=42). CONCLUSIONS: These findings suggest that increased eNO availability is required for statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, LV dysfunction, interstitial fibrosis, and survival after MI. eNO bioavailability after MI likely represents an important therapeutic target in heart failure after MI and mediates beneficial effects of statin treatment after MI.

Animals↗
PubMed2004

Allopurinol attenuates left ventricular remodeling and dysfunction after experimental myocardial infarction: a new action for an old drug?

BACKGROUND: Accumulating evidence suggests a critical role for increased reactive oxygen species (ROS) production in left ventricular (LV) remodeling and dysfunction after myocardial infarction (MI). Increased expression of xanthine oxidase (XO), a major source of ROS, has recently been demonstrated in experimental and clinical heart failure; however, a potential role for LV remodeling processes remains unclear. We therefore studied the effect of long-term treatment with allopurinol, a potent XO inhibitor, on myocardial ROS production and LV remodeling and dysfunction after MI. METHODS AND RESULTS: Mice with extensive anterior MI (n=105) were randomized to treatment with either vehicle or allopurinol (20 mg x kg(-1) x d(-1) by gavage) for 4 weeks starting on day 1 after surgery. Infarct size was similar among the groups. XO expression and activity were markedly increased in the remote myocardium of mice after MI, as determined by electron spin resonance spectroscopy. Myocardial ROS production was increased after MI but markedly reduced after allopurinol treatment. Importantly, allopurinol treatment substantially attenuated LV cavity dilatation and dysfunction after MI, as assessed by echocardiography, and markedly reduced myocardial hypertrophy and interstitial fibrosis. CONCLUSIONS: The present study reveals a novel beneficial effect of treatment with allopurinol, ie, a marked attenuation of LV remodeling processes and dysfunction after experimental MI. Allopurinol treatment therefore represents a potential novel strategy to prevent LV remodeling and dysfunction after MI.

Allopurinol↗
PubMed2004

Heme oxygenase-1 inhibition of MAP kinases, calcineurin/NFAT signaling, and hypertrophy in cardiac myocytes.

OBJECTIVE: Heme oxygenases (HO) are the rate-limiting enzymes in heme degradation, catalyzing the breakdown of heme to equimolar quantities of biliverdin (BV), carbon monoxide (CO), and ferrous iron. The inducible HO isoform, HO-1, confers protection against ischemia/reperfusion (I/R)-injury in the heart. We hypothesized that HO-1 and its catalytic by-products constitute an antihypertrophic signaling module in cardiac myocytes. METHODS AND RESULTS: The G protein-coupled receptor (GPCR) agonist endothelin-1 (ET-1) (30 nmol/l) stimulated a robust hypertrophic response in cardiac myocytes isolated from 1- to 3-day-old Sprague-Dawley rats, with increases in cell surface area (planimetry), sarcomere assembly (confocal laser scanning microscopy), and prepro-atrial natriuretic peptide (ANP) mRNA expression. Adenoviral overexpression of HO-1, but not beta-galactosidase, significantly inhibited ET-1 induced cardiac myocyte hypertrophy. The antihypertrophic effects of HO-1 were mimicked by BV (10 micromol/l) and the CO-releasing molecule [Ru(CO)3Cl2]2 (10 micromol/l), strongly suggesting a critical involvement of BV and CO in the antihypertrophic effects of HO-1. Both BV and CO suppressed extracellular signal-regulated kinases (ERK1/ERK2) and p38 mitogen-activated protein kinase (MAPK) activation by ET-1 stimulation. Moreover, BV and CO inhibited the prohypertrophic calcineurin/NFAT pathway. This inhibition occurred upstream from calcineurin because BV and CO inhibited NFAT activation in response to ET-1 stimulation but not in response to adenoviral expression of a constitutively active calcineurin mutant. Upstream-inhibition of the calcineurin/NFAT pathway by CO occurred independent from cGMP and cGMP-dependent protein kinase type I (PKG I). CONCLUSIONS: Heme oxygenase-1 and its catalytic by-products, BV and CO, constitute a novel antihypertrophic signaling pathway in cardiac myocytes. Biliverdin and CO inhibition of MAPKs and calcineurin/NFAT signaling provides a mechanistic framework how heme degradation products may promote their antihypertrophic effects.

Animals↗
PubMed2004

Comparative effects of AT1-antagonism and angiotensin-converting enzyme inhibition on markers of inflammation and platelet aggregation in patients with coronary artery disease.

OBJECTIVES: We evaluated whether renin-angiotensin system (RAS) blockade attenuates cardiovascular events. BACKGROUND: Because inflammation and enhanced thrombogenesis are hallmarks of atherosclerosis, we assessed whether RAS inhibition elicits anti-inflammatory and anti-aggregatory effects. METHODS: Interleukin 6 (IL-6), high-sensitivity C-reactive protein (hsCRP), metalloprotease 9 (MMP-9), and interleukin 10 (IL-10) were determined in patients with coronary artery disease (CAD) and arterial hypertension six to eight weeks after coronary angioplasty (low-density lipoprotein serum levels <150 mg/dl). Patients were randomized double-blind to either 20 mg enalapril (ENAL, n = 27) or 300 mg irbesartan (IRB, n = 21) for 3 months. Blood samples were drawn at baseline and at three months. Thromboxane A2-induced platelet aggregation was determined turbidimetrically; urine bicyclo-prostaglandin E2 (PGE(2)) and inflammatory markers were measured by enzyme-linked immunosorbent assay technique. RESULTS: Both treatment regimens enhanced serum IL-10 levels (IRB p < 0.001, ENAL p < 0.03) and reduced serum MMP-9 protein (IRB p < 0.001, ENAL p < 0.05) and MMP-9 activity (IRB p < 0.005, ENAL p < 0.05). Only IRB reduced serum IL-6 and hsCRP levels significantly compared with baseline (p < 0.01), whereas ENAL did not (hsCRP p < 0.02 IRB vs. ENAL, p < 0.01 IRB vs. ENAL). Platelet aggregation was only reduced by IRB (p < 0.001, ENAL p < 0.06, IRB vs. ENAL p < 0.001) while urine PGE(2) levels remained unchanged. CONCLUSIONS: Angiotensin-converting enzyme (ACE) inhibition and angiotensin II type 1 receptor (AT1) blockade reduced serum MMP-9 protein/activity to a similar extent, and only AT1 blockade reduced hsCRP, IL-6, and platelet aggregation in patients with CAD. Thus, AT1-blockade appears to exert stronger systemic anti-inflammatory and anti-aggregatory effects compared with ACE inhibition.

Angiotensin II Type 1 Receptor Blockers↗