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  • Increased fibulin-5 and elastin in S100A4/Mts1 mice with pulmonary hypertension CIRCULATION RESEARCH Merklinger, S. L., Wagner, R. A., Spiekerkoetter, E., Hinek, A., Knutsen, R. H., Kabir, M. G., Desai, K., Hacker, S., Wang, L. L., Cann, G. M., Ambartsumian, N. S., Lukanidin, E., Bernstein, D., Husain, M., Mecham, R. P., Starcher, B., Yanagisawa, H., Rabinovitch, M. 2005; 97 (6): 596-604

    Abstract

    Transgenic mice overexpressing the calcium binding protein, S100A4/Mts1, occasionally develop severe pulmonary vascular obstructive disease. To understand what underlies this propensity, we compared the pulmonary vascular hemodynamic and structural features of S100A4/Mts1 with control C57Bl/6 mice at baseline, following a 2-week exposure to chronic hypoxia, and after 1 and 3 months "recovery" in room air. S100A4/Mts1 mice had greater right ventricular systolic pressure and right ventricular hypertrophy at baseline, which increased further with chronic hypoxia and was sustained after 3 months "recovery" in room air. These findings correlated with a heightened response to acute hypoxia and failure to vasodilate with nitric oxide or oxygen. S100A4/Mts1 mice, when compared with C57Bl/6 mice, also had impaired cardiac function judged by reduced ventricular elastance and decreased cardiac output. Despite higher right ventricular systolic pressures with chronic hypoxia, S100A4/Mts1 mice did not develop more severe PVD, but in contrast to C57Bl/6 mice, these features did not regress on return to room air. Microarray analysis of lung tissue identified a number of genes differentially upregulated in S100A4/Mts1 versus control mice. One of these, fibulin-5, is a matrix component necessary for normal elastin fiber assembly. Fibulin-5 was localized to pulmonary arteries and associated with thickened elastic laminae. This feature could underlie attenuation of pulmonary vascular changes in response to elevated pressure, as well as impaired reversibility.

    View details for DOI 10.1161/01.RES.00000182425.49768.8a

    View details for Web of Science ID 000231896500013

    View details for PubMedID 16109920

  • Fibulin-5 may protect against pulmonary vascular obliterative disease in mice overexpressing Mts1 (S100A4) Merklinger, S. L., Wagner, R. A., Knutsen, R. H., Kabir, G., Desai, K., Hacker, S., Cann, G. M., Ambartsumian, N., Lukanidin, E., Husain, M., Mecham, R. P., Yanagisawa, H., Rabinovitch, M. LIPPINCOTT WILLIAMS & WILKINS. 2004: 19
  • Transgenic mice with arterial smooth muscle cell-specific conditional deletion of the bone morphogenetic protein type IA receptor (BMPRIA/ALK3) are hyporesponsive to hypoxia 77th Scientific Meeting of the American-Heart-Association El-Bizri, N., Wang, L. L., Merklinger, S. L., Desai, K., Rountree, R. B., Mishina, Y., RABINOVITCH, M. LIPPINCOTT WILLIAMS & WILKINS. 2004: 132?32
  • Conditional expression of a G(i)-coupled receptor causes ventricular conduction delay and a lethal cardiomyopathy PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Redfern, C. H., Degtyarev, M. Y., Kwa, A. T., Salomonis, N., Cotte, N., Nanevicz, T., Fidelman, N., Desai, K., Vranizan, K., Lee, E. K., Coward, P., Shah, N., Warrington, J. A., Fishman, G. I., Bernstein, D., Baker, A. J., Conklin, B. R. 2000; 97 (9): 4826-4831

    Abstract

    Cardiomyopathy is a major cause of morbidity and mortality. Ventricular conduction delay, as shown by prolonged deflections in the electrocardiogram caused by delayed ventricular contraction (wide QRS complex), is a common feature of cardiomyopathy and is associated with a poor prognosis. Although the G(i)-signaling pathway is up-regulated in certain cardiomyopathies, previous studies suggested this up-regulation was compensatory rather than a potential cause of the disease. Using the tetracycline transactivator system and a modified G(i)-coupled receptor (Ro1), we provide evidence that increased G(i) signaling in mice can result in a lethal cardiomyopathy associated with a wide QRS complex arrhythmia. Induced expression of Ro1 in adult mice resulted in a >90% mortality rate at 16 wk, whereas suppression of Ro1 expression after 8 wk protected mice from further mortality and allowed partial improvement in systolic function. Results of DNA-array analysis of over 6,000 genes from hearts expressing Ro1 are consistent with hyperactive G(i) signaling. DNA-array analysis also identified known markers of cardiomyopathy and hundreds of previously unknown potential diagnostic markers and therapeutic targets for this syndrome. Our system allows cardiomyopathy to be induced and reversed in adult mice, providing an unprecedented opportunity to dissect the role of G(i) signaling in causing cardiac pathology.

    View details for Web of Science ID 000086703000078

    View details for PubMedID 10781088

    View details for PubMedCentralID PMC18317

  • Targeted disruption of the beta 2 adrenergic receptor gene JOURNAL OF BIOLOGICAL CHEMISTRY Chruscinski, A. J., Rohrer, D. K., Schauble, E., Desai, K. H., Bernstein, D., Kobilka, B. K. 1999; 274 (24): 16694-16700

    Abstract

    beta-Adrenergic receptors (beta-ARs) are members of the superfamily of G-protein-coupled receptors that mediate the effects of catecholamines in the sympathetic nervous system. Three distinct beta-AR subtypes have been identified (beta1-AR, beta2-AR, and beta3-AR). In order to define further the role of the different beta-AR subtypes, we have used gene targeting to inactivate selectively the beta2-AR gene in mice. Based on intercrosses of heterozygous knockout (beta2-AR +/-) mice, there is no prenatal lethality associated with this mutation. Adult knockout mice (beta2-AR -/-) appear grossly normal and are fertile. Their resting heart rate and blood pressure are normal, and they have a normal chronotropic response to the beta-AR agonist isoproterenol. The hypotensive response to isoproterenol, however, is significantly blunted compared with wild type mice. Despite this defect in vasodilation, beta2-AR -/- mice can still exercise normally and actually have a greater total exercise capacity than wild type mice. At comparable workloads, beta2-AR -/- mice had a lower respiratory exchange ratio than wild type mice suggesting a difference in energy metabolism. beta2-AR -/- mice become hypertensive during exercise and exhibit a greater hypertensive response to epinephrine compared with wild type mice. In summary, the primary physiologic consequences of the beta2-AR gene disruption are observed only during the stress of exercise and are the result of alterations in both vascular tone and energy metabolism.

    View details for Web of Science ID 000080780400007

    View details for PubMedID 10358008

  • Phospholamban deficiency does not compromise exercise capacity. American journal of physiology. Heart and circulatory physiology Desai, K. H., Schauble, E., Luo, W., Kranias, E., Bernstein, D. 1999; 276 (4): H1172?H1177

    Abstract

    Deficiency of phospholamban (PLB) results in enhancement of basal murine cardiac function and an attenuated response to beta-adrenergic stimulation. To determine whether the absence of PLB also reduces the reserve capacity of the murine cardiovascular system to respond to stress, we evaluated the heart rate (HR), blood pressure, and metabolic responses of PLB-deficient (PLB-/-) mice to graded treadmill exercise (GTE). PLB-/- mice were hypertensive at rest (125 19 vs. 109 16 mmHg, P < 0.05) but had normal tachycardic and hypotensive responses to isoproterenol. The HR response to GTE was normal; however, the hypertension in PLB-/- mice normalized at peak exercise. Their exercise capacities, as measured by duration of exercise and peak oxygen consumption (V?o 2), were normal. The oxygen pulse (V?o 2/HR) curve was also normal in PLB-/- mice, suggesting an ability to appropriately increase stroke volume and oxygen extraction during GTE, despite an inability to increase beta-adrenergically stimulated cardiac contractility. Thus deficiency of PLB, although resulting in diminished beta-adrenergic inotropic reserve, does not compromise cardiac performance during exercise.

    View details for DOI 10.1152/ajpheart.1999.276.4.H1172

    View details for PubMedID 29598207

  • Role of beta-adrenergic signaling in exercise conditioning in mice Ruwitch, L., Schauble, E., Desai, K., Kobilka, B., Bernstein, D. INT PEDIATRIC RESEARCH FOUNDATION, INC. 1999: 30A
  • Phospholamban deficiency does not compromise exercise capacity AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Desai, K. H., Schauble, E., Luo, W. S., Kranias, E., Bernstein, D. 1999; 276 (4): H1172-H1177

    Abstract

    Deficiency of phospholamban (PLB) results in enhancement of basal murine cardiac function and an attenuated response to beta-adrenergic stimulation. To determine whether the absence of PLB also reduces the reserve capacity of the murine cardiovascular system to respond to stress, we evaluated the heart rate (HR), blood pressure, and metabolic responses of PLB-deficient (PLB-/-) mice to graded treadmill exercise (GTE). PLB-/- mice were hypertensive at rest (125 +/- 19 vs. 109 +/- 16 mmHg, P < 0.05) but had normal tachycardic and hypotensive responses to isoproterenol. The HR response to GTE was normal; however, the hypertension in PLB-/- mice normalized at peak exercise. Their exercise capacities, as measured by duration of exercise and peak oxygen consumption (VO2), were normal. The oxygen pulse (VO2/HR) curve was also normal in PLB-/- mice, suggesting an ability to appropriately increase stroke volume and oxygen extraction during GTE, despite an inability to increase beta-adrenergically stimulated cardiac contractility. Thus deficiency of PLB, although resulting in diminished beta-adrenergic inotropic reserve, does not compromise cardiac performance during exercise.

    View details for Web of Science ID 000079554200009

    View details for PubMedID 10199840

  • Inducible and reversible dilated cardiomyopathy in transgenic mice expressing a modified G(i)-coupled receptor Redfern, C. H., Degtyarev, M. Y., Desai, K., Coward, P. S., Lee, E. K., Kwa, A., Fishman, G. I., Bernstein, D., Baker, A. J., Conklin, B. R. AMER SOC CELL BIOLOGY. 1998: 362A?362A
  • Alterations in dynamic heart rate control in the beta(1)-adrenergic receptor knockout mouse AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Rohrer, D. K., Schauble, E. H., Desai, K. H., Kobilka, B. K., Bernstein, D. 1998; 274 (4): H1184-H1193

    Abstract

    beta 1-Adrenergic receptors (beta 1-ARs) are key targets of sympathetic nervous system activity and play a major role in the beat-to-beat regulation of cardiac chronotropy and inotropy. We employed a beta 1-AR gene knockout model to test the hypothesis that beta 1-AR function is critical for maintenance of resting heart rate and baroreflex responsiveness and, on the basis of its important role in regulating chronotropy and inotropy, is also required for maximal exercise capacity. Using an awake unrestrained mouse model, we demonstrate that resting heart rate and blood pressure are normal in beta 1-AR knockouts and that the qualitative responses to baroreflex stimulation are intact. Chronotropic reserve in beta 1-AR knockouts is markedly limited, with peak heart rates approximately 200 beats/min less than wild types. During graded treadmill exercise, heart rate is significantly depressed in beta 1-AR knockouts at all work loads, but despite this limitation, there are no reductions in maximal exercise capacity or metabolic indexes. Thus, in mice, the beta 1-AR is not essential for either maintenance of resting heart rate or for maximally stressed cardiovascular performance.

    View details for Web of Science ID 000072839800015

    View details for PubMedID 9575921

  • Alterations in dynamic heart rate control in the beta1-adrenergic receptor knockout mouse. American journal of physiology. Heart and circulatory physiology Rohrer, D. K., Schauble, E. H., Desai, K. H., Kobilka, B. K., Bernstein, D. 1998; 274 (4): H1184?H1193

    Abstract

    beta1-Adrenergic receptors (beta1-ARs) are key targets of sympathetic nervous system activity and play a major role in the beat-to-beat regulation of cardiac chronotropy and inotropy. We employed a beta1-AR gene knockout model to test the hypothesis that beta1-AR function is critical for maintenance of resting heart rate and baroreflex responsiveness and, on the basis of its important role in regulating chronotropy and inotropy, is also required for maximal exercise capacity. Using an awake unrestrained mouse model, we demonstrate that resting heart rate and blood pressure are normal in beta1-AR knockouts and that the qualitative responses to baroreflex stimulation are intact. Chronotropic reserve in beta1-AR knockouts is markedly limited, with peak heart rates 200 beats/min less than wild types. During graded treadmill exercise, heart rate is significantly depressed in beta1-AR knockouts at all work loads, but despite this limitation, there are no reductions in maximal exercise capacity or metabolic indexes. Thus, in mice, the beta1-AR is not essential for either maintenance of resting heart rate or for maximally stressed cardiovascular performance.

    View details for DOI 10.1152/ajpheart.1998.274.4.H1184

    View details for PubMedID 29585980

  • Cardiovascular indexes in the mouse at rest and with exercise: New tools to study models of cardiac disease AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Desai, K. H., Sato, R., Schauble, E., Barsh, G. S., Kobilka, B. K., Bernstein, D. 1997; 272 (2): H1053-H1061

    Abstract

    Manipulations of the murine genome that alter cardiovascular function have created the need for methods to study cardiovascular physiology in genetically altered animals in vivo. We adapted chronic physiological measurement techniques to the nonanesthetized, nonrestrained murine model, established strain-specific cardiovascular and metabolic norms, and evaluated responses to anesthesia, exercise, and adrenergic stimulation. Anesthesia resulted in alterations in heart rate (HR), blood pressure (BP), and O2 consumption (V(O2)) and CO2 production (V(CO2)) for up to 6 h postoperatively. There were significant interstrain differences in resting values of HR and BP Graded treadmill exercise resulted in linear increases in HR, V(O2), V(CO2), and respiratory exchange ratio (RER) similar to those seen in larger species. Response to beta-adrenergic stimulation showed a classic sigmoidal dose-response curve; however, there was very little tachycardiac response to vagal blockade, indicating low resting vagal tone. This study demonstrates the feasibility of performing chronic cardiovascular measurements in nonanesthetized mice and stresses the importance of allowing for anesthetic recovery and strain variability. Murine cardiovascular responses to exercise can be reliably measured and are qualitatively similar to those in humans.

    View details for Web of Science ID A1997WJ80900057

    View details for PubMedID 9124413

  • Cardiovascular regulation in mice lacking alpha(2)-adrenergic receptor subtypes b and c SCIENCE Link, R. E., Desai, K., Hein, L., Stevens, M. E., Chruscinski, A., Bernstein, D., Barsh, G. S., Kobilka, B. K. 1996; 273 (5276): 803-805

    Abstract

    alpha2-Adrenergic receptors (alpha2ARs) are essential components of the neural circuitry regulating cardiovascular function. The role of specific alpha2AR subtypes (alpha2a, alpha2b, and alpha2c) was characterized with hemodynamic measurements obtained from strains of genetically engineered mice deficient in either alpha2b or alpha2c receptors. Stimulation of alpha2b receptors in vascular smooth muscle produced hypertension and counteracted the clinically beneficial hypotensive effect of stimulating alpha2a receptors in the central nervous system. There were no hemodynamic effects produced by disruption of the alpha2c subtype. These results provide evidence for the clinical efficacy of more subtype-selective alpha2AR drugs.

    View details for Web of Science ID A1996VB42900045

    View details for PubMedID 8670422

  • Targeted disruption of the mouse beta 1-adrenergic receptor gene: Developmental and cardiovascular effects PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Rohrer, D. K., Desai, K. H., Jasper, J. R., Stevens, M. E., Regula, D. P., Barsh, G. S., Bernstein, D., Kobilka, B. K. 1996; 93 (14): 7375-7380

    Abstract

    At least three distinct beta-adrenergic receptor (beta-AR) subtypes exist in mammals. These receptors modulate a wide variety of processes, from development and behavior, to cardiac function, metabolism, and smooth muscle tone. To understand the roles that individual beta-AR subtypes play in these processes, we have used the technique of gene targeting to create homozygous beta 1-AR null mutants (beta 1-AR -/-) in mice. The majority of beta 1-AR -/- mice die prenatally, and the penetrance of lethality shows strain dependence. Beta l-AR -/- mice that do survive to adulthood appear normal, but lack the chronotropic and inotropic responses seen in wild-type mice when beta-AR agonists such as isoproterenol are administered. Moreover, this lack of responsiveness is accompanied by markedly reduced stimulation of adenylate cyclase in cardiac membranes from beta 1-AR -/- mice. These findings occur despite persistent cardiac beta 2-AR expression, demonstrating the importance of beta 1-ARs for proper mouse development and cardiac function, while highlighting functional differences between beta-AR subtypes.

    View details for Web of Science ID A1996UW79200098

    View details for PubMedID 8693001

  • COLCHICINE AND CYTOCHALASIN-B ENHANCE CYCLIC-AMP ACCUMULATION VIA POSTRECEPTOR ACTIONS JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Jasper, J. R., Post, S. R., Desai, K. H., Insel, P. A., Bernstein, D. 1995; 274 (2): 937-942

    Abstract

    The role of cytoskeletal microtubules and microfilaments in modulating cAMP generation in S49 lymphoma cells was investigated using the agents colchicine and cytochalasin B, respectively, which are known to disrupt these structures. A 1-hr pretreatment of S49 cells with 10 microM colchicine typically enhanced maximal isoproterenol-(beta-adrenergic receptor) stimulated cAMP accumulation by 100%, whereas cytochalasin B increased isoproterenol-stimulated cAMP by 30%. The combination of colchicine and cytochalasin B synergistically enhanced agonist-stimulated cAMP to 225% over control values. A synergistic increase in cAMP accumulation was also observed in cells treated with the agonist prostaglandin E1 or cholera toxin (which activates the stimulatory guanine nucleotide regulatory (Gs) protein). Colchicine and cytochalasin B did not ablate the inhibitory effects of somatostatin or the stimulatory effect of pertussis toxin treatment on beta-receptor-stimulated cAMP accumulation, indicating that these cytoskeletal disrupting agents do not enhance responsiveness in S49 cells via alterations in the inhibitory guanine nucleotide regulatory protein pathway. Moreover, colchicine, but not cytochalasin B treatment, enhances expression of isoproterenol-promoted 3H-forskolin binding in intact cells (a measure of Gs/adenylyl cyclase coupling). Thus, colchicine and cytochalasin B appear to enhance signaling in the Gs/adenylyl cyclase pathway by alterations of components distal to hormone receptors, most likely at the Gs protein and/or via cAMP generation. These results imply that microtubules and microfilaments can interact in the regulation of this pathway and that increases in cellular cAMP may contribute to the action of drugs that alter function of these cytoskeletal elements.

    View details for Web of Science ID A1995RN98300048

    View details for PubMedID 7636757

  • RESTING AND STRESSED CARDIORESPIRATORY PARAMETERS IN THE MOUSE - NEW TOOLS FOR THE ASSESSMENT OF TRANSGENIC MODELS Desai, K., Kobilka, B., Barsh, G., Bernstein, D. NATURE PUBLISHING GROUP. 1994: A33?A33

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