Biomedical subjects

Maurits A Jansen

Publications and source records attributed to Maurits A Jansen.

5 recordsLinked to original sources

PubMed2006

Combined blockade of the Na+ channel and the Na+/H+ exchanger virtually prevents ischemic Na+ overload in rat hearts.

Blocking either the Na(+) channel or the Na(+)/H(+) exchanger (NHE) has been shown to reduce Na(+) and Ca(2+) overload during myocardial ischemia and reperfusion, respectively, and to improve post-ischemic contractile recovery. The effect of combined blockade of both Na(+) influx routes on ionic homeostasis is unknown and was tested in this study. [Na(+)](i), pH(i) and energy-related phosphates were measured using simultaneous (23)Na- and (31)P-NMR spectroscopy in isolated rat hearts. Eniporide (3 muM) and/or lidocaine (200 muM) were administered during 5 min prior to 40 min of global ischemia and 40 min of drug free reperfusion to block the NHE and the Na(+) channel, respectively. Lidocaine reduced the rise in [Na(+)](i) during the first 10 min of ischemia, followed by a rise with a rate similar to the one found in untreated hearts. Eniporide reduced the ischemic Na(+) influx during the entire ischemic period. Administration of both drugs resulted in a summation of the effects found in the lidocaine and eniporide groups. Contractile recovery and infarct size were significantly improved in hearts treated with both drugs, although not significantly different from hearts treated with either one of them.

Animals↗

PubMed2006

Endoglin has a crucial role in blood cell-mediated vascular repair.

BACKGROUND: Endoglin, an accessory receptor for transforming growth factor-beta in vascular endothelial cells, is essential for angiogenesis during mouse development. Mutations in the human gene cause hereditary hemorrhagic telangiectasia type 1 (HHT1), a disease characterized by vascular malformations that increase with age. Although haploinsufficiency is the underlying cause of the disease, HHT1 individuals show great heterogeneity in age of onset, clinical manifestations, and severity. METHODS AND RESULTS: In situ hybridization and immunohistochemical analysis of mouse and human hearts revealed that endoglin is upregulated in neoangiogenic vessels formed after myocardial infarction. Microvascularity within the infarct zone was strikingly lower in mice with reduced levels of endoglin (Eng+/-) compared with wild-type mice, which resulted in a greater deterioration in cardiac function as measured by magnetic resonance imaging. This did not appear to be because of defects in host inflammatory cell numbers in the infarct zone, which accumulated to a similar extent in wild-type and heterozygous mice. However, defects in vessel formation and heart function in Eng+/- mice were rescued by injection of mononuclear cells from healthy human donors but not by mononuclear cells from HHT1 patients. CONCLUSIONS: These results establish defective vascular repair as a significant component of the origin of HHT1. Because vascular damage or inflammation occurs randomly, it may also explain disease heterogeneity. More generally, the efficiency of vascular repair may vary between individuals because of intrinsic differences in their mononuclear cells.

Animals↗

PubMed2006

MEF2 activates a genetic program promoting chamber dilation and contractile dysfunction in calcineurin-induced heart failure.

BACKGROUND: Hypertrophic growth, a risk factor for mortality in heart disease, is driven by reprogramming of cardiac gene expression. Although the transcription factor myocyte enhancer factor-2 (MEF2) is a common end point for several hypertrophic pathways, its precise cardiac gene targets and function in cardiac remodeling remain to be elucidated. METHODS AND RESULTS: We report the existence of synergistic interactions between the nuclear factor of activated T cells and MEF2 transcription factors triggered by calcineurin signaling. To circumvent the embryonic lethality and mitochondrial deficiency associated with germ-line null mutations for MEF2C and MEF2A respectively, we used conditional transgenesis to express a dominant-negative form of MEF2 in the murine postnatal heart and combined this with magnetic resonance imaging to assess MEF2 transcriptional function in Ca2+/calcineurin-induced cardiac remodeling. Surprisingly, end-diastolic and end-systolic ventricular dimensions and contractility were normalized in the presence of severely hypertrophied left ventricular walls on MEF2 inhibition in calcineurin transgenic mice. In line, we generated lines of transgenic mice expressing MEF2A in the heart, which displayed primarily chamber dilation. Microarray profiling indicated that MEF2 promotes a gene profile functioning primarily to or at the nucleus, cytoskeletal and microtubular networks, and mitochondria. CONCLUSIONS: These findings assign a novel function to MEF2 transcription factors in the postnatal heart, where they activate a genetic program that minimally affects cardiac growth yet promotes chamber dilation, mechanical dysfunction, and dilated cardiomyopathy.

Animals↗

PubMed2004

Assessment of myocardial viability by intracellular 23Na magnetic resonance imaging.

BACKGROUND: Because of rapid changes in myocardial intracellular Na+ (Na+(i)) during ischemia and reperfusion (R), 23Na magnetic resonance imaging (MRI) appears to be an ideal diagnostic modality for early detection of myocardial ischemia and viability. So far, cardiac 23Na MRI data are limited and mostly concerned with imaging of total Na+. For proper interpretation, imaging of both Na+(i) and extracellular Na+ is essential. In this study, we tested whether Na+(i) imaging can be used to assess viability after low-flow (LF) ischemia. METHODS AND RESULTS: Isolated rat hearts were subjected to LF (1%, 2%, or 3% of control coronary flow) and R. A shift reagent was used to separate Na+(i) and extracellular Na+ resonances. Acquisition-weighted 23Na chemical shift imaging (CSI) was alternated with 23Na MR spectroscopy. Already during control perfusion, Na+(i) could be clearly seen on the images. Na+(i) image intensity increased with increasing severity of ischemia. During R, Na+(i) image intensity remained highest in 1% LF hearts. Not only did we find very good correlations between Na+(i) image intensity at end-R and end-diastolic pressure (R=0.85, P<0.001) and recovery of the rate-pressure product (R=-0.88, P<0.001) at end-R, but most interestingly, also Na+(i) image intensity at end-LF was well correlated with end-diastolic pressure (R=0.78, P<0.01) and with recovery of the rate-pressure product (R=-0.81, P<0.01) at end-R. Furthermore, Na+(i) image intensity at end-LF was well correlated with creatine kinase release during R (R=0.79, P<0.05) as well as with infarct size (R=0.77, P<0.05). CONCLUSIONS: These data indicate that 23Na CSI is a promising tool for the assessment of myocardial viability.

Animals↗

PubMed2003

Energy requirements for the Na+ gradient in the oxygenated isolated heart: effect of changing the free energy of ATP hydrolysis.

This study tests the hypothesis that a decrease of the free energy of ATP hydrolysis (Delta GATP) below a threshold value will inhibit Na+-K+-ATPase (Na+ pump) activity and result in an increase of intracellular Na+ concentration ([Na+]i) in the heart. Conditions were designed in which hearts were solely dependent on ATP derived from oxidative phosphorylation. The only substrate supplied was the fatty acid butyrate (Bu) at either low, 0.1 mM (LowBu), or high, 4 mM (HighBu), concentrations. Escalating work demand reduced the Delta GATP of the LowBu hearts. 31P, 23Na, and 87Rb NMR spectroscopy measured high-energy phosphate metabolites, [Na+]i, and Rb+ uptake. Rb+ uptake was used to estimate Na+ pump activity. To measure [Na+]i using a shift reagent for cations, extracellular Ca2+ was reduced to 0.85 mM, which eliminated work demand Delta GATP reductions. Increasing extracellular Na+ (Nae+) to 200 mM restored work demand Delta GATP reductions. In response to higher [Na+]e, [Na+]i increased equally in LowBu and HighBu hearts to approximately 8.6 mM, but Delta GATP decreased only in LowBu hearts. At lowest work demand the LowBu heart Delta GATP was -53 kJ/mol, Rb+ uptake was similar to that of HighBu hearts, and [Na+]i was constant. At highest work demand the LowBu heart Delta GATP decreased to -48 kJ/mol, the [Na+]i increased to 25 mM, and Rb+ uptake was 56% of that in HighBu hearts. At the highest work demand the HighBu heart Delta GATP was -54 kJ/mol and [Na+]i increased only approximately 10%. We conclude that a Delta GATP below -50 kJ/mol limits the Na+ pump and prevents maintenance of [Na+]i homeostasis.

Adenosine Triphosphate↗