Pulmonary Vasodilator Response to Adrenomedullin in Patients with Pulmonary Hypertension

Nagaya, Noritoshi; Miyatake, Kunio; Kyotani, Shingo; Nishikimi, Toshio; Nakanishi, Norifumi; Kangawa, Kenji

doi:10.1291/hypres.26.s141

Cited by 32 publications

(15 citation statements)

References 25 publications

(25 reference statements)

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“…Because endothelial dysfunction may play a role in the pathogenesis of pulmonary hypertension such as PPH (3), pulmonary endothelial cells may be a therapeutic target for the treatment of pulmonary hypertension. We have demonstrated that administration of AM peptide decreases pulmonary vascular resistance in patients with PPH (45,46,48,51). Thus we investigated the effects of AM gene-modified EPCs on pulmonary hypertension in rats (44).…”

Section: Therapeutic Angiogenesismentioning

confidence: 99%

Adrenomedullin: angiogenesis and gene therapy

Nagaya¹,

Mori²,

Murakami³

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

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Adrenomedullin (AM) is a potent, long-lasting vasodilator peptide that was originally isolated from human pheochromocytoma. AM signaling is of particular significance in endothelial cell biology since the peptide protects cells from apoptosis, promotes angiogenesis, and affects vascular tone and permeability. The angiogenic effect of AM is mediated by activation of Akt, mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2, and focal adhesion kinase in endothelial cells. Both AM and its receptor, calcitonin receptor-like receptor, are upregulated through a hypoxia-inducible factor-1-dependent pathway under hypoxic conditions. Thus AM signaling plays an important role in the regulation of angiogenesis in hypoxic conditions. Recently, we have developed a nonviral vector, gelatin. Positively charged gelatin holds negatively charged plasmid DNA in its lattice structure. DNA-gelatin complexes can delay gene degradation, leading to efficient gene transfer. Administration of AM DNA-gelatin complexes induces potent angiogenic effects in a rabbit model of hindlimb ischemia. Thus gelatin-mediated AM gene transfer may be a new therapeutic strategy for the treatment of tissue ischemia. Endothelial progenitor cells (EPCs) play an important role in endothelial regeneration. Interestingly, EPCs phagocytose ionically linked DNA-gelatin complexes in coculture, which allows nonviral gene transfer into EPCs. AM gene transfer into EPCs inhibits cell apoptosis and induces proliferation and migration, suggesting that AM gene transfer strengthens the therapeutic potential of EPCs. Intravenous administration of AM gene-modified EPCs regenerate pulmonary endothelium, resulting in improvement of pulmonary hypertension. These results suggest that in vivo and in vitro transfer of AM gene using gelatin may be applicable for intractable cardiovascular disease.

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Section: Therapeutic Angiogenesismentioning

confidence: 99%

Adrenomedullin: angiogenesis and gene therapy

Nagaya¹,

Mori²,

Murakami³

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Also it is a new tool for use in diagnosis of extracellular volume in renal insufficiency [63]. AM seems to have the potential to protect organs from damage, since AM supplementation was effective to improve hemodynamics in patients with congestive heart failure and hypertension [64][65][66][67].…”

Section: Ammentioning

confidence: 99%

Adrenomedullin and its Related Peptide

Shimosawa

Fujita

2005

Endocr J

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MORE than 100 years have passed since Riva-Rocci [1] modified the sphygmograph by Marey [2], Mahomed [3] and Von Basch [4] to make conventional blood pressure measurements possible. Two years after the method was established, existence of hypertensive agents, now known as renin, was reported [5]. Since then laboratory investigations as well as clinical and epidemiological studies in hypertension research have been advancing at an exponential rate [6]. Since the 1950s, several circulation-regulating peptides, both hypertensive and hypotensive, were discovered. Among them, a novel vasodilative peptide, adrenomedullin (AM) was isolated from pheochromocytoma tissue in 1993 [7]. Another processing site in a propeptide of AM was found and a new hypotensive peptide, named proadrenomedullin N-terminal 20 peptide (PAMP), was isolated from human plasma and urine [7,8].Blood circulates throughout the body by the pressure force generated by cardiac output and peripheral resistance. Each of these primary determinants of blood pressure is determined by the interaction of an exceedingly complex series of factors. Thus it is crucial to determine this complex of interactions in order to better understand the physiological role of these newly found factors. AM and PAMPAs mentioned above, AM, originally isolated from pheochromocytoma cell, is also produced and secreted in endothelial cells [7,19], and has been shown to exhibit hypotensive action by direct vasodilation via both the elevation of intracellular cAMP and alteration of calcium sensitivity in vascular smooth muscle cells [20]. Besides these actions, recent studies have shown that AM increases nitric oxide synthesis in endothelial cell by elevating intracellular calcium [21][22][23][24]. Studies on the physiological action of AM have also revealed that AM increases intracellular cAMP [22] [28]. Moreover, AM inhibits smooth muscle cell migration and proliferation [29, 30]. AM also shares a slight homology with CGRP and the above mentioned physiological effects are inhibited by CGRP antagonist CGRP(8-37) [21]. Together with the evidence that AM production is increased in failing heart [31, 32], it is speculated that

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“…At physiological concentration, ADM was shown to have potent vasodilator effect in the systemic and pulmonary circulations (13)(14)(15). In many cell types, including endothelial and smooth muscle cells of the vascular wall, production and secretion of ADM are increased in response to cellular strain induced by hypoxia and ischemia (16)(17)(18).…”

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confidence: 99%

Plasma Adrenomedullin and Allelic Variation in the ADM Gene and Kidney Disease in People With Type 2 Diabetes

et al. 2015

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Production of adrenomedullin (ADM), a vasodilator peptide, increases in response to ischemia and hypoxia in the vascular wall and the kidney. This may be an adaptive response providing protection against organ damage. We investigated the hypothesis that ADM has a nephroprotective effect in two prospective cohorts of patients with type 2 diabetes recruited in France. The highest tertile of plasma MR-proADM (a surrogate for ADM) concentration at baseline was associated with the risk of renal outcomes (doubling of plasma creatinine concentration and/or progression to end-stage renal disease) during follow-up in both cohorts. Four SNPs in the ADM gene region were associated with plasma MR-proADM concentration at baseline and with eGFR during follow-up in both cohorts. The alleles associated with lower eGFR were also associated with lower plasma MR-proADM level. In conclusion, plasma MR-proADM concentration was associated with renal outcome in patients with type 2 diabetes. Our data suggest that the ADM gene modulates the genetic susceptibility to nephropathy progression. Results are consistent with the hypothesis of a reactive rise of ADM in diabetic nephropathy, blunted in risk alleles carriers, and with a nephroprotective effect of ADM. A possible therapeutic effect of ADM receptor agonists in diabetic renal disease would be worth investigating.

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Pulmonary Vasodilator Response to Adrenomedullin in Patients with Pulmonary Hypertension

Cited by 32 publications

References 25 publications

Adrenomedullin: angiogenesis and gene therapy

Adrenomedullin: angiogenesis and gene therapy

Adrenomedullin and its Related Peptide

Plasma Adrenomedullin and Allelic Variation in the ADM Gene and Kidney Disease in People With Type 2 Diabetes

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