Biomedical subjects

Mansoor Husain

Publications and source records attributed to Mansoor Husain.

26 records · Page 2Linked to original sources

PubMed2003

The Iroquois homeobox gene Irx2 is not essential for normal development of the heart and midbrain-hindbrain boundary in mice.

The Iroquois homeobox (Irx) genes have been implicated in the specification and patterning of several organs in Drosophila and several vertebrate species. Misexpression studies of chick, Xenopus, and zebra fish embryos have demonstrated that Irx genes are involved in the specification of the midbrain-hindbrain boundary. All six murine Irx genes are expressed in the developing heart, suggesting that they might possess distinct functions during heart development, and a role for Irx4 in normal heart development has been recently demonstrated by gene-targeting experiments. Here we describe the generation and phenotypic analysis of an Irx2-deficient mouse strain. By targeted insertion of a lacZ reporter gene into the Irx2 locus, we show that lacZ expression reproduces most of the endogenous Irx2 expression pattern. Despite the dynamic expression of Irx2 in the developing heart, nervous system, and other organs, Irx2-deficient mice are viable, are fertile, and appear to be normal. Although chick Irx2 has been implicated in the development of the midbrain-hindbrain region, we show that Irx2-deficient mice develop a normal midbrain-hindbrain boundary. Furthermore, Irx2-deficient mice have normal cardiac morphology and function. Functional compensation by other Irx genes might account for the absence of a phenotype in Irx2-deficient mice. Further studies of mutant mice of other Irx genes as well as compound mutant mice will be necessary to uncover the functional roles of these evolutionarily conserved transcriptional regulators in development and disease.

Animals↗

PubMed2003

Cardiac function in mice lacking the glucagon-like peptide-1 receptor.

Glucagon-like peptide-1 (GLP-1) acts via its G protein-coupled receptor (GLP-1R) to regulate blood glucose. Although the GLP-1R is widely expressed in peripheral tissues, including the heart, and exogenous GLP-1 administration increases heart rate and blood pressure in rodents, the physiological importance of GLP-1R action in the cardiovascular system remains unclear. We now show that 2-month-old mice with genetic deletion of the GLP-1R (GLP-1R(-/-)) exhibit reduced resting heart rate and elevated left ventricular (LV) end diastolic pressure compared with CD-1 wild-type controls. At the age of 5 months, echocardiography and histology demonstrate increased LV thickness in GLP-1R(-/-) mice. Although baseline hemodynamic parameters of GLP-1R(-/-) did not differ significantly from those of wild type, GLP-1R(-/-) mice displayed impaired LV contractility and diastolic function after insulin administration. The defective cardiovascular response to insulin was not attributable to a generalized defect in the stress response, because GLP-1R(-/-) mice responded appropriately to insulin with increased c-fos expression in the hypothalamus and increased circulating levels of glucagon and epinephrine. Furthermore, LV contractility after exogenous epinephrine infusion was also reduced in GLP-1R(-/-) mice. These findings provide new evidence implicating an essential role for GLP-1R in the control of murine cardiac structure and function in vivo.

Animals↗

PubMed2002

Reversible regional wall motion abnormalities on exercise technetium-99m-gated cardiac single photon emission computed tomography predict high-grade angiographic stenoses.

OBJECTIVES: We sought to determine the level of angiographic stenosis at which reversible regional wall motion abnormalities (RWMA) are present on exercise stress technetium-99m (Tc-99m)- gated single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI), and whether assessments of stress and rest RWMA add incremental diagnostic information. BACKGROUND: Stress and rest gated SPECT MPI enables the detection of post-exercise stunning. Although some studies have correlated RWMA to the severity of MPI defects, only one previous study correlated RWMA on gated MPI to angiographic findings. However, this correlation excluded patients with rest perfusion defects and did not involve gating of rest images. METHODS: One hundred patients undergoing angiography within six months of exercise stress Tc-99m (sestamibi)-gated SPECT MPI (in the absence of interim cardiac events or revascularization) were recruited. Images were acquired 15 to 30 min after stress and interpreted without knowledge of the Duke treadmill score, left ventricular ejection fraction and angiographic data. RESULTS: The sensitivity of reversible RWMA for angiographic stenoses >70% was 53%, with a specificity of 100%. The presence of reversible RWMA was able to stratify patients with angiographic stenoses of 50% to 79% and 80% to 99% with a high positive predictive value. A good correlation was noted between the presence of reversible RWMA and the coronary artery jeopardy score (R = 0.49, p < 0.0001). Multivariate analysis showed that the post-stress RWMA, Duke treadmill and reversible RWMA scores were significant predictors of angiographic severity. CONCLUSIONS: Post-stress and reversible RWMA, as shown by exercise stress Tc-99m-gated SPECT MPI, are significant predictors of angiographic disease and add incremental value to MPI for the assessment of angiographic severity.

Age Factors↗

PubMed2002

Overexpression of the serine elastase inhibitor elafin protects transgenic mice from hypoxic pulmonary hypertension.

BACKGROUND: Increased serine elastase activity has been implicated in the vascular remodeling associated with chronic hypoxia-related pulmonary hypertension in rats. METHODS AND RESULTS: In this study we determined the time course of hypoxia-induced serine elastase activity in the murine lung and related this to initiation of a proteolytic cascade characterized by an increase in matrix metalloproteinases (MMPs). We then used transgenic mice in which overexpression of the selective serine elastase inhibitor elafin was targeted to the cardiovascular system to determine whether upregulation of a naturally occurring serine elastase inhibitor suppresses MMPs and the hemodynamic and structural response to chronic hypoxia (air at 380 mm Hg). In nontransgenic but not in elafin-transgenic mice, we documented a transient increase in serine elastase activity after 12 hours of hypoxic exposure attributed to a 30-kDa protein as determined by elastin zymography and fluorophosphonate/fluorophosphate-biotin labeling. Two days after hypoxia, the pro-forms of MMP-2 and MMP-9 were induced in the nontransgenic mice, but MMP-9 was suppressed in elafin-transgenic mice. Acute hypoxic vasoconstriction was similar in nontransgenic and elafin-transgenic littermates. Chronic hypoxia for 26 days resulted in >1-fold increase in right ventricular pressure (P<0.004) in nontransgenic compared with control or elafin-transgenic littermates. In the latter mice, normalization of the right ventricular pressure was associated with reduced muscularization and preservation of the number of distal vessels (P<0.04 for both comparisons). CONCLUSIONS: Modulation of the severity of chronic hypoxia-induced pulmonary vascular disease could be a function of endogenously expressed serine elastase inhibitors.

Actins↗

PubMed2002

The role of NOS in heart failure: lessons from murine genetic models.

Nitric Oxide Synthases (NOSs) are a group of related proteins that produce nitric oxide (NO). In mammals, there are three known members of this gene family: nNOS (NOS1), iNOS (NOS2) and eNOS (NOS3). Each has been disrupted by targeted gene ablation in mice and the corresponding phenotypes examined. These mice have allowed an examination of the contribution of each NOS in a variety of experimental models and continue to provided insights into the patho-physiological role of NOS and NO. With increasing sophistication, murine transgenic approaches continue to offer a wealth of information, and invaluable tools to further study the NOS system. The focus of this review will be an examination of the tools available, and the insights gained from studies done on murine NOS genetic models in the context of heart failure.

Animals↗

PubMed2002

Effects of age, gender, and blood pressure on myogenic responses of mesenteric arteries from C57BL/6 mice.

The myogenic response (MR) may represent an important physiological parameter underlying arterial blood pressure (BP). We studied the effects of age, gender, and BP on the MR of mesenteric arteries from 8- to 52-wk-old mice. Increasing age and BP are associated with an increase in the perfusion pressure at which tone develops (myogenic set point). An inverse correlation exists between age and extent (magnitude) of the MR in male (r(2) = 0.93, P = 0.0087) and female mice (r(2) = 0.90, P = 0.013) as well as between BP and extent of the MR in male (r(2) = 0.96, P = 0.0036) and female (r(2) = 0.90, P = 0.014) mice. In contrast, the strength of the MR (slope of active diameter-pressure relationship) and phenylephrine-mediated constriction did not differ among these groups. Although gender had no effect on MR at any perfusion pressure or age, only male mice showed significant salt-induced hypertension and an associated increase in the set point and reduction in the extent of the MR. The set point and extent of the MR is linked to the in vivo pressure during development and experimental hypertension.

Aging↗

PubMed2002

Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation, heart block, and sudden death.

Increased inducible nitric oxide synthase (iNOS) expression is a component of the immune response and has been demonstrated in cardiomyocytes in septic shock, myocarditis, transplant rejection, ischemia, and dilated cardiomyopathy. To explore whether the consequences of such expression are adaptive or pathogenic, we have generated a transgenic mouse model conditionally targeting the expression of a human iNOS cDNA to myocardium. Chronic cardiac-specific upregulation of iNOS in transgenic mice led to increased production of peroxynitrite. This was associated with a mild inflammatory cell infiltrate, cardiac fibrosis, hypertrophy, and dilatation. While iNOS-overexpressing mice infrequently developed overt heart failure, they displayed a high incidence of sudden cardiac death due to bradyarrhythmia. This dramatic cardiac phenotype was rescued by specific attenuation of transgene activity. These data implicate cardiomyocyte iNOS overexpression as sufficient to cause cardiomyopathy, bradyarrhythmia, and sudden cardiac death.

Acetylcholinesterase↗

PubMed2002

Differential regulation of gonadotropin-releasing hormone secretion and gene expression by androgen: membrane versus nuclear receptor activation.

Steroid hormones induce rapid membrane receptor-mediated effects that appear to be separate from long-term genomic events. The membrane receptor-mediated effects of androgens on GT1-7 GnRH-secreting neurons were examined. We observed androgen binding activity with a cell-impermeable BSA-conjugated testosterone [testosterone 3-(O-carboxymethyl)oxime (T-3-BSA)] and were able to detect a 110-kDa protein recognized by the androgen receptor (AR) monoclonal MA1-150 antibody in the plasma membrane fraction of the GT1-7 cells by Western analysis. Further, a transfected green fluorescent protein-tagged AR translocates and colocalizes to the plasma membrane of the GT1-7 neuron. Treatment with 10 nM 5alpha-dihydrotestosterone (DHT) inhibits forskolin-stimulated accumulation of cAMP, through a pertussis toxin-sensitive G protein, but has no effect on basal cAMP levels. The inhibition of forskolin-stimulated cAMP accumulation by DHT was blocked by hydroxyflutamide, a specific inhibitor of the nuclear AR. DHT, testosterone (T), and T-3-BSA, all caused significant elevations in intracellular calcium concentrations ([Ca(2+)](i)). T-3-BSA stimulates GnRH secretion 2-fold in the GT1-7 neuron, as did DHT or T. Interestingly GnRH mRNA levels were down-regulated by DHT and T as has been reported, but not by treatment with T-3-BSA or testosterone 17beta-hemisuccinate BSA. These studies indicate that androgen can differentially regulate GnRH secretion and gene expression through specific membrane-mediated or nuclear mechanisms.

1-Methyl-3-isobutylxanthine↗