Treatment With Growth Hormone Enhances Contractile Reserve and Intracellular Calcium Transients in Myocytes From Rats With Postinfarction Heart Failure

Tajima, Masahiro; Weinberg, Ellen O.; Bartúnek, Jozef; Jin, Hongkui; Yang, Renhui; Paoni, Nicholas F.; Lorell, Beverly H.

doi:10.1161/01.cir.99.1.127

Cited by 104 publications

(74 citation statements)

References 51 publications

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“…[1][2][3][4] Moreover, the recent demonstration of a direct SERCA-2 upregulation in Akt-over- Akt and calcium handling A Cittadini et al expressing mice 11 is in part supported by our data demonstrating a significant increase of SERCA-2 protein in Ad.Akt-infected rats. This finding, which was also observed in rats following exogenous GH administration, 24 provides potential molecular underpinnings for the contractility and Ca 2+ handling changes observed in the current study. In fact, SERCA-2 overexpression is known to increase Ca 2+ transport and cardiac function, and is mainly characterized by increased systolic Ca 2+ levels, shorter transients, enhanced contractility with accelerated rates of contraction and relaxation, and no evidence of diastolic Ca 2+ overload consistent with the enhanced capacity of the SR to sequester calcium.…”

Section: Comparison With Previous Studiessupporting

confidence: 85%

Adenoviral gene transfer of Akt enhances myocardial contractility and intracellular calcium handling

et al. 2005

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The serine-threonine kinase Akt/PKB mediates stimuli from different classes of cardiomyocyte receptors, including the growth hormone/insulin like growth factor and the b-adrenergic receptors. Whereas the growth-promoting and antiapoptotic properties of Akt activation are well established, little is known about the effects of Akt on myocardial contractility, intracellular calcium (Ca 2+ ) handling, oxygen consumption, and b-adrenergic pathway. To this aim, Sprague-Dawley rats were subjected to a wild-type Akt in vivo adenoviral gene transfer using a catheter-based technique combined with aortopulmonary crossclamping. Left ventricular (LV) contractility and intracellular Ca 2+ handling were evaluated in an isolated isovolumic bufferperfused, aequorin-loaded whole heart preparations 10 days after the surgery. The Ca 2+ -force relationship was obtained under steady-state conditions in tetanized muscles. No significant hypertrophy was detected in adenovirus with wild-type Akt (Ad.Akt) versus controls rats (LV-to-body weight ratio 2.670.2 versus 2.770.1 mg/g, controls versus Ad.Akt, P, NS). LV contractility, measured as developed pressure, increased by 41% in Ad.Akt. This was accounted for by both more systolic Ca 2+ available to the contractile machinery (+19% versus controls) and by enhanced myofilament Ca 2+ responsiveness, documented by an increased maximal Ca 2+ -activated pressure (+19% versus controls) and a shift to the left of the Ca 2+ -force relationship. Such increased contractility was paralleled by a slight increase of myocardial oxygen consumption (14%), while titrated dose of dobutamine providing similar inotropic effect augmented oxygen consumption by 39% (Po0.01). Phospholamban, calsequestrin, and ryanodine receptor LV mRNA and protein content were not different among the study groups, while sarcoplasmic reticulum Ca 2+ ATPase protein levels were significantly increased in Ad.Akt rats. b-Adrenergic receptor density, affinity, kinase-1 levels, and adenylyl cyclase activity were similar in the three animal groups. In conclusion, our results support an important role for Akt/PKB in the regulation of myocardial contractility and mechanoenergetics.

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Section: Comparison With Previous Studiessupporting

confidence: 85%

Adenoviral gene transfer of Akt enhances myocardial contractility and intracellular calcium handling

et al. 2005

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“…Additionally, activation of the GH/IGF-1 axis increased myocardial contractility, decreased peripheral vascular resistance (1,6,8,32,38), promoted physiological myocardial hypertrophy (34), and upregulated sarco(endo)plasmic reticulum Ca 2ϩ -ATPase 2a (33) in heart failure. In the present study, RV IGF-1 mRNA levels were increased in the MCT group, which might suggest a local increase, dependent of RV overload.…”

Section: Discussionmentioning

confidence: 99%

Endogenous production of ghrelin and beneficial effects of its exogenous administration in monocrotaline-induced pulmonary hypertension

Henriques‐Coelho¹,

Correia‐Pinto²,

Roncon‐Albuquerque³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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-Moreira. Endogenous production of ghrelin and beneficial effects of its exogenous administration in monocrotaline-induced pulmonary hypertension. Am J Physiol Heart Circ Physiol 287: H2885-H2890, 2004; doi:10.1152/ ajpheart.01122.2003.-We investigated the endogenous production of ghrelin as well as cardiac and pulmonary vascular effects of its administration in a rat model of monocrotaline (MCT)-induced pulmonary hypertension (PH). Adult Wistar rats randomly received a subcutaneous injection of MCT (60 mg/kg) or an equal volume of vehicle. One week later, animals were randomly assigned to receive a subcutaneous injection of ghrelin (100 g/kg bid for 2 wk) or saline. Four groups were analyzed: normal rats treated with ghrelin (n ϭ 7), normal rats injected with saline (n ϭ 7), MCT rats treated with ghrelin (n ϭ 9), and MCT rats injected with saline (n ϭ 9). At 22-25 days, right (RV) and left ventricular (LV) pressures were measured, heart and lungs were weighted, and samples were collected for histological and molecular analysis. Endogenous production of ghrelin was almost abolished in normal rats treated with ghrelin. In MCT-treated animals, pulmonary expression of ghrelin was preserved, and RV myocardial expression was increased more than 20 times. In these animals, exogenous administration of ghrelin attenuated PH, RV hypertrophy, wall thickening of peripheral pulmonary arteries, and RV diastolic disturbances and ameliorated LV dysfunction, without affecting its endogenous production. In conclusion, decreased tissular expression of ghrelin in healthy animals but not in PH animals suggests a negative feedback in the former that is lost in the latter. A selective increase of ghrelin mRNA levels in the RV of animals with PH might indicate distinct regulation of its cardiac expression. Finally, ghrelin administration attenuated MCT-induced PH, pulmonary vascular remodeling, and RV hypertrophy, indicating that it may modulate PH. myocardial hypertrophy; ventricular hemodymamics; pulmonary vasculature PULMONARY HYPERTENSION (PH) is a progressive disease associated with right ventricular (RV) hypertrophy that commonly progresses to heart failure. Endothelin (ET)-1 and several other neurohumoral agents play a central role in the complex pathophysiology of PH (11,28) and are used as therapeutic targets for this entity. For instance, several authors observed that ET-1 antagonism decreases PH, restores endothelial metabolic function, inhibits RV hypertrophy, and improves survival both in experimental (5,19,26) and clinical (27) settings.

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“…Twenty micrograms of RNA from aortic stenosis mice treated with cyclosporine, aortic stenosis mice treated with no drug, and age-matched controls was subjected to Northern blot hybridization as previously described, 13 using a 60-bp oligonucleotide probe complementary to the coding region of mouse atrial natriuretic factor (ANF) and a 1.4-kb mouse GAPDH cDNA probe (Ambion). Signals were captured by autoradiography and analyzed by ImageQuant software (Molecular Dynamics).…”

Section: Northern Blot Analysesmentioning

confidence: 99%

Pressure Overload Induces Severe Hypertrophy in Mice Treated With Cyclosporine, an Inhibitor of Calcineurin

Ding

Price

Borg

et al. 1999

Circulation Research

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134

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Abstract-Cardiac hypertrophy is the fundamental adaptation of the adult heart to mechanical load. Recent work has shown that inhibition of calcineurin activity with cyclosporine suppresses the development of hypertrophy in calcineurin transgenic mice and in in vitro systems of neonatal rat cardiocytes stimulated with peptide growth factors. To test the hypothesis that the calcineurin signaling pathway is critical for load-induced hypertrophy in vivo, we examined the effects of cyclosporine treatment on left ventricular hypertrophy induced by experimental ascending aortic stenosis for 4 weeks in mice. Left ventricular systolic pressure was elevated to a similar level in aortic stenosis mice that were treated with cyclosporine versus no drug. Left ventricular mass and myocyte size were similar in treated and untreated aortic stenosis animals and significantly greater than control animals, showing that cyclosporine treatment does not suppress hypertrophic growth. Both treated and untreated animals showed increased left ventricular expression of the load-sensitive gene atrial natriuretic factor. Calcineurin activity was measured in the left ventricle and the spleen from control mice and aortic stenosis mice treated with cyclosporine versus no drug. Levels of calcineurin activity were similar in the spleens of control and untreated aortic stenosis mice. However, calcineurin activity was severely depressed in left ventricular tissue of untreated aortic stenosis mice compared with control mice and was further reduced by cyclosporine treatment. Thus, pathological hypertrophy and cardiac-restricted gene expression induced by pressure overload in vivo are not suppressed by treatment with cyclosporine and do not appear to depend on the elevation of left ventricular calcineurin activity. (Circ Res. 1999;84:729-734.)

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Treatment With Growth Hormone Enhances Contractile Reserve and Intracellular Calcium Transients in Myocytes From Rats With Postinfarction Heart Failure

Cited by 104 publications

References 51 publications

Adenoviral gene transfer of Akt enhances myocardial contractility and intracellular calcium handling

Adenoviral gene transfer of Akt enhances myocardial contractility and intracellular calcium handling

Endogenous production of ghrelin and beneficial effects of its exogenous administration in monocrotaline-induced pulmonary hypertension

Pressure Overload Induces Severe Hypertrophy in Mice Treated With Cyclosporine, an Inhibitor of Calcineurin

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