284 research outputs found
Biomarkers in acute coronary syndromes and their role in diabetic patients
Diabetic patients with acute coronary syndromes
are at high risk for cardiovascular complications
but risk stratification in these patients remains
challenging. Regularly, diabetic patients have a less typical
clinical presentation, which could lead to delayed
diagnosis and subsequent delayed initiation of treatment.
Since diabetic patients derive particular benefit
from aggressive anti-platelet therapy, early diagnostic
and therapeutic risk stratification of these patients is of
critical importance to improve their adverse outcome.
Although the electrocardiogram remains a pivotal
diagnostic tool in the evaluation of patients suspected of
having an acute coronary syndrome, only significant STsegment
changes provide reasonable prognostic information.
Therefore, repeated assessment of circulating
protein biomarkers represents a valuable diagnostic tool
for improving efficacy and safety of decision-making in
these patients. The combined use of biomarkers reflecting
distinct pathophysiological aspects, such as myocardial
necrosis, vascular inflammation, oxidative stress
and neurohumoral activation, may significantly improve
triage of patients with chest pain. These tools may identify
those patients that are at particularly high risk for
short-term and/or long-term cardiovascular events.
Eventually, tailored medical and interventional treatment
of diabetic patients should help to prevent these cardiac
events in a cost-effective manner
Comparative transcriptome analysis of embryonic and adult stem cells with extended and limited differentiation capacity
Comparison of the transcriptomes of pluripotent embryonic stem cells, multipotent adult progenitor cells and lineage restricted mesenchymal stem cells identified a unique gene expression profile of multipotent adult progenitor cells
Plasticity and cardiovascular applications of multipotent adult progenitor cells
Cardiovascular disease is the leading cause of death worldwide, which
has encouraged the search for new therapies that enable the treatment of
patients in palliative and curative ways. In the past decade, the potential
benefit of transplantation of cells that are able to substitute for the injured
tissue has been studied with several cell populations, such as stem cells.
Some of these cell populations, such as myoblasts and bone marrow cells,
are already being used in clinical trials. The laboratory of CM Verfaillie has
studied primitive progenitors, termed multipotent adult progenitor cells,
which can be isolated from adult bone marrow. These cells can differentiate
in vitro at the single-cell level into functional cells that belong to the three
germ layers and contribute to most, if not all, somatic cell types after
blastocyst injection. This remarkably broad differentiation potential makes
this particular cell population a candidate for transplantation in tissues
in need of regeneration. Here, we focus on the regenerative capacity of
multipotent adult progenitor cells in several ischemic mouse models, such
as acute and chronic myocardial infarction and limb ischemia
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Increased Cardiac Myocyte PDE5 Levels in Human and Murine Pressure Overload Hypertrophy Contribute to Adverse LV Remodeling
Background: The intracellular second messenger cGMP protects the heart under pathological conditions. We examined expression of phosphodiesterase 5 (PDE5), an enzyme that hydrolyzes cGMP, in human and mouse hearts subjected to sustained left ventricular (LV) pressure overload. We also determined the role of cardiac myocyte-specific PDE5 expression in adverse LV remodeling in mice after transverse aortic constriction (TAC). Methodology/Principal Findings: In patients with severe aortic stenosis (AS) undergoing valve replacement, we detected greater myocardial PDE5 expression than in control hearts. We observed robust expression in scattered cardiac myocytes of those AS patients with higher LV filling pressures and BNP serum levels. Following TAC, we detected similar, focal PDE5 expression in cardiac myocytes of C57BL/6NTac mice exhibiting the most pronounced LV remodeling. To examine the effect of cell-specific PDE5 expression, we subjected transgenic mice with cardiac myocyte-specific PDE5 overexpression (PDE5-TG) to TAC. LV hypertrophy and fibrosis were similar as in WT, but PDE5-TG had increased cardiac dimensions, and decreased dP/dtmax and dP/dtmin with prolonged tau (P<0.05 for all). Greater cardiac dysfunction in PDE5-TG was associated with reduced myocardial cGMP and SERCA2 levels, and higher passive force in cardiac myocytes in vitro. Conclusions/Significance: Myocardial PDE5 expression is increased in the hearts of humans and mice with chronic pressure overload. Increased cardiac myocyte-specific PDE5 expression is a molecular hallmark in hypertrophic hearts with contractile failure, and represents an important therapeutic target
Circulating endothelial cells are an early predictor in renal cell carcinoma for tumor response to sunitinib
<p>Abstract</p> <p>Background</p> <p>Tyrosine kinase inhibitors (TKI) have enriched the therapeutic options in patients with renal cell carcinoma (RCC), which frequently induce morphological changes in tumors. However, only little is known about the biological activity of TKI. Circulating endothelial cells (CEC) have been associated with endothelial damage and, hence, may serve as a putative marker for the biological activity of TKI. The main objective of our study was to evaluate the predictive value of CEC, monocytes, and soluble vascular endothelial growth factor receptor (sVEGFR)-2 in RCC patients receiving sunitinib treatment.</p> <p>Methods</p> <p>Analyses of CEC, monocytes, and sVEGFR-2 were accomplished for twenty-six consecutive patients with metastatic RCC who received treatment with sunitinib (50 mg, 4 wks on 2 wks off schedule) at our institution in 2005 and 2006.</p> <p>Results</p> <p>In RCC patients CEC are elevated to 49 ± 44/ml (control 8 ± 8/ml; P = 0.0001). Treatment with sunitinib is associated with an increase in CEC within 28 days of treatment in patients with a Progression free survival (PFS) above the median to 111 ± 61 (P = 0.0109), whereas changes in patients with a PFS below the median remain insignificant 69 ± 61/ml (P = 0.1848). Monocytes and sVEGFR2 are frequently altered upon sunitinib treatment, but fail to correlate with clinical response, defined by PFS above or below the median.</p> <p>Conclusions</p> <p>Sunitinib treatment is associated with an early increase of CEC in responding patients, suggesting superior endothelial cell damage in these patients as a putative predictive biomarker.</p
Placenta Growth Factor-1 Exerts Time-Dependent Stabilization of Adherens Junctions Following VEGF-Induced Vascular Permeability
Increased vascular permeability is an early event characteristic of tissue ischemia and angiogenesis. Although VEGF family members are potent promoters of endothelial permeability the role of placental growth factor (PlGF) is hotly debated. Here we investigated PlGF isoforms 1 and 2 and present in vitro and in vivo evidence that PlGF-1, but not PlGF-2, can inhibit VEGF-induced permeability but only during a critical window post-VEGF exposure. PlGF-1 promotes VE-cadherin expression via the trans-activating Sp1 and Sp3 interaction with the VE-cadherin promoter and subsequently stabilizes transendothelial junctions, but only after activation of endothelial cells by VEGF. PlGF-1 regulates vascular permeability associated with the rapid localization of VE-cadherin to the plasma membrane and dephosphorylation of tyrosine residues that precedes changes observed in claudin 5 tyrosine phosphorylation and membrane localization. The critical window during which PlGF-1 exerts its effect on VEGF-induced permeability highlights the importance of the translational significance of this work in that PLGF-1 likely serves as an endogenous anti-permeability factor whose effectiveness is limited to a precise time point following vascular injury. Clinical approaches that would pattern nature's approach would thus limit treatments to precise intervals following injury and bring attention to use of agents only during therapeutic windows
Cardiogenesis with a focus on vasculogenesis and angiogenesis
The initial intraembryonic vasculogenesis occurs in the cardiogenic mesoderm. Here, a cell population of proendocardial cells detaches from the mesoderm that subsequently generates the single endocardial tube by forming vascular plexuses. In the course of embryogenesis, the endocardium retains vasculogenic, angiogenic and haematopoietic potential. The coronary blood vessels that sustain the rapidly expanding myocardium develop in the course of the formation of the cardiac loop by vasculogenesis and angiogenesis from progenitor cells of the proepicardial serosa at the venous pole of the heart as well as from the endocardium and endothelial cells of the sinus venosus. Prospective coronary endothelial cells and progenitor cells of the coronary blood vessel walls (smooth muscle cells, perivascular cells) originate from different cell populations that are in close spatial as well as regulatory connection with each other. Vasculo‐ and angiogenesis of the coronary blood vessels are for a large part regulated by the epicardium and epicardium‐derived cells. Vasculogenic and angiogenic signalling pathways include the vascular endothelial growth factors, the angiopoietins and the fibroblast growth factors and their receptors
Soluble CD59 Expressed from an Adenovirus In Vivo Is a Potent Inhibitor of Complement Deposition on Murine Liver Vascular Endothelium
Inappropriate activation of complement on the vascular endothelium of specific organs, or systemically, underlies the etiology of a number of diseases. These disorders include atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis, atherosclerosis, age-related macular degeneration, diabetic retinopathy, and transplant rejection. Inhibition of the terminal step of complement activation, i.e. formation of the membrane attack complex, using CD59 has the advantage of retaining the upstream processes of the complement cascade necessary for fighting pathogens and retaining complement's crucial role in tissue homeostasis. Previous studies have shown the necessity of membrane targeting of soluble CD59 in order for it to prove an effective inhibitor of complement deposition both in vitro and in vivo. In this study we have generated an in vivo model of human complement activation on murine liver vascular endothelium. This model should prove useful for the development of anti-complement therapies for complement-induced pathologies of vascular endothelium. Using this model, we have demonstrated the viability of a non membrane-targeted soluble CD59 to significantly inhibit complement deposition on the endothelium of murine liver vasculature when expressed in vivo from an adenovirus. This result, unanticipated based on prior studies, suggests that the use of non membrane-targeted sCD59 as an anti-complement therapy be re-visited
Multipotent adult progenitor cells sustain function of ischemic limbs in mice
Despite progress in cardiovascular research, a cure for peripheral vascular disease has not been found. We compared
the vascularization and tissue regeneration potential of murine and human undifferentiated multipotent
adult progenitor cells (mMAPC-U and hMAPC-U), murine MAPC-derived vascular progenitors (mMAPC-VP),
and unselected murine BM cells (mBMCs) in mice with moderate limb ischemia, reminiscent of intermittent
claudication in human patients. mMAPC-U durably restored blood flow and muscle function and stimulated
muscle regeneration, by direct and trophic contribution to vascular and skeletal muscle growth. This was in
contrast to mBMCs and mMAPC-VP, which did not affect muscle regeneration and provided only limited and
transient improvement. Moreover, mBMCs participated in a sustained inflammatory response in the lower
limb, associated with progressive deterioration in muscle function. Importantly, mMAPC-U and hMAPC-U also
remedied vascular and muscular deficiency in severe limb ischemia, representative of critical limb ischemia in
humans. Thus, unlike BMCs or vascular-committed progenitors, undifferentiated multipotent adult progenitor
cells offer the potential to durably repair ischemic damage in peripheral vascular disease patients
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