Mitochondria act as a reservoir for the basic amine HIPDM in the lung

Miniati, Massimo; Paci, A; Cocci, Franca; Ciarimboli, Giuliano; Monti, Simonetta

doi:10.1183/09031936.96.09112306

Cited by 13 publications

(18 citation statements)

References 32 publications

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“…Previous studies have used the basic amine N-N-N9-trimethyl-N9(2-hydroxy-3-methyl-5-iodobenzyl)-1,3 propanediamine labeled with radioactive iodine ( 123 I-HIPDM) for lung imaging (11,12). 123 I-HIPDM is extracted by the lungs and, contrary to 99m Tc-AM-L, displayed increased retention in a model of pulmonary hypertension induced by pulmonary vein banding (11).…”

Section: Discussionmentioning

confidence: 99%

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Molecular Imaging of Monocrotaline-Induced Pulmonary Vascular Disease with Radiolabeled Linear Adrenomedullin

Dupuis

Harel

et al. 2009

J Nucl Med

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No test currently exists for molecular imaging of pulmonary arterial hypertension (PAH). Adrenomedullin is a vasodilator peptide predominantly cleared by pulmonary endothelial receptors. We developed a linear adrenomedullin derivative radiolabeled with 99m Tc ( 99m Tc-AM-L) for imaging of pulmonary circulation and tested its capacity to detect anomalies of pulmonary circulation caused by PAH. Methods: PAH was induced by monocrotaline in rats and compared with controls. After 5 wk, 99m Tc-AM-L was injected intravenously. Plasma kinetics were measured, lung activity was determined in vivo after 30 min using a nuclear camera, and lung activity was determined ex vivo in explanted lungs. Expression of adrenomedullin receptors was measured in lung homogenates. Results: The plasma levels of 99m Tc-AM-L significantly increased in PAH by approximately 2-fold. Uptake by the lungs was homogeneous but greatly reduced in PAH by about 70%. In vivo retention was 14% 6 1% (mean 6 SD) of the injected dose in controls and 4% 6 1% in PAH (P , 0.0001). A similar reduction was measured ex vivo (6.0 6 1.6 percentage injected dose per gram [%ID/g] vs. 0.95 6 0.21 %ID/g, P , 0.0001). The expression of the heterodimeric component of the adrenomedullin receptor, receptor activity modifying protein 2, was also greatly reduced in PAH lungs (P , 0.001). Interestingly, right ventricular uptake of 99m Tc-AM-L was increased by PAH (P 5 0.02) and correlated with the degree of right ventricular hypertrophy (r 5 0.83, P 5 0.001). Conclusion: Pulmonary uptake of 99m Tc-AM-L is greatly reduced in monocrotaline-induced PAH. This novel molecular imaging agent may be useful in the diagnosis and follow-up of pulmonary vascular disorders. No clinically available test currently exists that can provide both anatomic and functional information on the status of pulmonary circulation. Pulmonary arterial hypertension (PAH) is a disorder characterized by endothelial dysfunction, with intimal and vascular smooth muscle proliferation leading to gradual obliteration of pulmonary arterioles (1). PAH is screened by transthoracic Doppler echocardiography, with the estimation of pulmonary artery systolic pressure obtained using the tricuspid valve regurgitant jet. Although this approach correlates with hemodynamically measured pulmonary pressure, it does not provide direct information on the biology of pulmonary circulation and may miss the early presence of pulmonary vascular disease (1). The recent availability of oral therapies for PAH such as endothelin receptor antagonists and phophodiesterase inhibitors advocates for earlier diagnosis of this condition and treatment of subjects in functional class II (1). There is, therefore, a clinical need for novel diagnostic approaches toward pulmonary vascular disease that could provide an earlier and more precise diagnosis.Adrenomedullin is a vasodilator peptide produced by the vascular endothelium. When injected intravenously, adrenomedullin is predominantly cleared by pulmonary circulation by specific adrenomedullin rec...

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Section: Discussionmentioning

confidence: 99%

“…123 I-HIPDM is extracted by the lungs and, contrary to 99m Tc-AM-L, displayed increased retention in a model of pulmonary hypertension induced by pulmonary vein banding (11). 123 I-HIPDM is a lipophilic amine that concentrates in lung mitochondria (12) by a receptor-independent process.…”

Section: Discussionmentioning

confidence: 99%

Molecular Imaging of Monocrotaline-Induced Pulmonary Vascular Disease with Radiolabeled Linear Adrenomedullin

Dupuis

Harel

et al. 2009

J Nucl Med

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“…The compounds concentrating most in the lung are amines with a pKa greater than 8, collectively grouped under the term of basic amines [17]. [ 11 C]McN5652 is one of those amines, and a similar uptake in the lung was reported with other tracers such as [ 123 I]IMP [18,19] and [ 123 I]HIPDM [20,21]. Higher accumulation patterns in smokers were reported in other radio-labeled amine tracers such as [ 123 I]IMP [22], [ 123 I]HIPDM [23,24], and [ 99m Tc]HMPAO [25].…”

Section: Discussionmentioning

confidence: 77%

“…On the other hand, [ 125 I]HIPDM in BALF did not exceed 3% of total [ 125 I]HIPDM activity in a rabbit study, and most of [ 123 I]HIPDM was retained by lung tissue [21]. In the lung tissue, mitochondria is the predominant location in a subcellular distribution profi le of HIPDM [21]. Similar studies would be necessary to investigate the mechanism of the nonspecifi c accumulation of…”

Section: Discussionmentioning

confidence: 82%

“…It has been speculated that a persistent pool in the lung could result from the interaction with lung phospholipids, namely with alveolar surfactant [7,9]. On the other hand, [ 125 I]HIPDM in BALF did not exceed 3% of total [ 125 I]HIPDM activity in a rabbit study, and most of [ 123 I]HIPDM was retained by lung tissue [21]. In the lung tissue, mitochondria is the predominant location in a subcellular distribution profi le of HIPDM [21].…”

Section: Discussionmentioning

confidence: 95%

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Effects of smoking on the lung accumulation of [11C]McN5652

Takano¹,

Ito²,

Sudo³

et al. 2007

Ann Nucl Med

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Surface expression of a glycolytic enzyme, α‐enolase, recognized by autoantibodies in connective tissue disorders

et al. 2000

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In systemic autoimmune diseases, autoantibodies specific for α‐enolase are detected more frequently in patients with active renal involvement. To analyze the properties of anti‐α‐enolase antibodies and the distribution of the enzyme in the cell, mouse monoclonal and polyclonal antibodies were obtained from mice immunized with a glutathione‐S‐transferase‐α‐enolase fusion protein. Anti‐α‐enolase antibodies were purified from patient sera on enolase from human kidney. Using these antibodies, the distribution of α‐enolase in the cell was analyzed in subcellular fractions and in the cell membrane by flow cytometry and immunoprecipitation. Plasminogen binding was studied by an immunoenzymatic assay. We observed that α‐enolase was present in the cytosol and membrane fractions obtained from kidney and U937 cells. By flow cytometry, mouse polyclonal anti‐enolase antibodies, one monoclonal and 7/9 human anti‐enolase antibodies bound the membrane of U937 cells. One monoclonal antibody and mouse polyclonal anti‐enolase antibodies immunoprecipitated a 48‐kDa molecule from surface‐labeled U937 cells and this molecule was recognized by rabbit anti‐enolase antibodies. Both immunization‐induced antibodies and 7/9 autoantibodies from patient sera inhibited the binding of plasminogen to α‐enolase. The results show that α‐enolase, an autoantigen in connective tissue diseases, is a cytoplasmic enzyme which is also expressed on the cell membrane, with which it is strongly associated. Anti‐α‐enolase autoantibodies isolated from patient sera recognize the membrane‐associated form of the enzyme and/or interfere with its receptor function, thus inhibiting the binding of plasminogen. Autoantibodies specific for α‐enolase could play a pathogenic role, either by a cytopathic effect or by interfering with membrane fibrinolytic activity.

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Mitochondria act as a reservoir for the basic amine HIPDM in the lung

Cited by 13 publications

References 32 publications

Molecular Imaging of Monocrotaline-Induced Pulmonary Vascular Disease with Radiolabeled Linear Adrenomedullin

Molecular Imaging of Monocrotaline-Induced Pulmonary Vascular Disease with Radiolabeled Linear Adrenomedullin

Effects of smoking on the lung accumulation of [11C]McN5652

Surface expression of a glycolytic enzyme, α‐enolase, recognized by autoantibodies in connective tissue disorders

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