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Correale M, Tricarico L, Bevere EML, Chirivì F, Croella F, Severino P, Mercurio V, Magrì D, Dini F, Licordari R, Beltrami M, Dattilo G, Salzano A, Palazzuoli A. Circulating Biomarkers in Pulmonary Arterial Hypertension: An Update. Biomolecules 2024; 14:552. [PMID: 38785959 PMCID: PMC11117582 DOI: 10.3390/biom14050552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Revised: 04/25/2024] [Accepted: 05/01/2024] [Indexed: 05/25/2024] Open
Abstract
Pulmonary arterial hypertension (PAH) is a rare subtype of group 1 pulmonary hypertension (PH) diseases, characterized by high pulmonary artery pressure leading to right ventricular dysfunction and potential life-threatening consequences. PAH involves complex mechanisms: vasoconstriction, vascular remodeling, endothelial dysfunction, inflammation, oxidative stress, fibrosis, RV remodeling, cellular hypoxia, metabolic imbalance, and thrombosis. These mechanisms are mediated by several pathways, involving molecules like nitric oxide and prostacyclin. PAH diagnosis requires clinical evaluation and right heart catheterization, confirming a value of mPAP ≥ 20 mmHg at rest and often elevated pulmonary vascular resistance (PVR). Even if an early and accurate diagnosis is crucial, PAH still lacks effective biomarkers to assist in its diagnosis and prognosis. Biomarkers could contribute to arousing clinical suspicion and serve for prognosis prediction, risk stratification, and dynamic monitoring in patients with PAH. The aim of the present review is to report the main novelties on new possible biomarkers for the diagnosis, prognosis, and treatment monitoring of PAH.
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Affiliation(s)
- Michele Correale
- Cardiothoracic Department, Ospedali Riuniti University Hospital, 71100 Foggia, Italy
| | - Lucia Tricarico
- Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy; (L.T.); (E.M.L.B.); (F.C.)
| | - Ester Maria Lucia Bevere
- Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy; (L.T.); (E.M.L.B.); (F.C.)
| | - Francesco Chirivì
- Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy; (L.T.); (E.M.L.B.); (F.C.)
| | - Francesca Croella
- Cardiothoracic Vascular Department, Division of Provincial Cardiology, Santissima Annunziata Hospital and Delta Hospital, Azienda Unità Sanitaria Locale di Ferrara, 44121 Ferrara, Italy;
| | - Paolo Severino
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 00185 Rome, Italy;
| | - Valentina Mercurio
- Department of Translational Medical Sciences, Federico II University, 80138 Naples, Italy;
| | - Damiano Magrì
- Department of Clinical and Molecular Medicine, Azienda Ospedaliera Sant’Andrea, “Sapienza” Università degli Studi di Roma, 00161 Rome, Italy;
| | - Frank Dini
- Istituto Auxologico IRCCS, Centro Medico Sant’Agostino, Via Temperanza, 6, 20127 Milan, Italy;
- Department of Public Health and Clinical Medicine, Umeå University, 901 87 Umeå, Sweden
| | - Roberto Licordari
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Section of Cardiology, University of Messina, 98122 Messina, Italy; (R.L.); (G.D.)
| | - Matteo Beltrami
- Arrhythmia and Electrophysiology Unit, Careggi University Hospital, 50134 Florence, Italy;
| | - Giuseppe Dattilo
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Section of Cardiology, University of Messina, 98122 Messina, Italy; (R.L.); (G.D.)
| | - Andrea Salzano
- Cardiology Unit, AORN A Cardarelli, 80131 Naples, Italy;
| | - Alberto Palazzuoli
- Cardiovascular Diseases Unit, Cardio-Thoracic and Vascular Department, S. Maria alle Scotte Hospital, University of Siena, 53100 Siena, Italy;
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Jülke EM, Fischer JP, Els-Heindl S, Bierer D, Flamme I, Köbberling J, Riedl B, Beck-Sickinger AG. Rational design of highly stabilized and selective adrenomedullin analogs. J Pept Sci 2023; 29:e3530. [PMID: 37423610 DOI: 10.1002/psc.3530] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 06/19/2023] [Accepted: 06/20/2023] [Indexed: 07/11/2023]
Abstract
The peptide hormone adrenomedullin (ADM) consists of 52 amino acids with a disulfide bond and an amidated C-terminus. Due to the vasodilatory and cardioprotective effects, the agonistic activity of the peptide on the adrenomedullin 1 receptor (AM1 R) is of high pharmacological interest. However, the wild-type peptide shows low metabolic stability leading to rapid degradation in the cardiovascular system. Previous work by our group has identified proteolytic cleavage sites and demonstrated stabilization of ADM by lipidation, cyclization, and N-methylation. Nevertheless, these ADM analogs showed reduced activity and subtype selectivity toward the closely related calcitonin gene-related peptide receptor (CGRPR). Here, we report on the rational development of ADM derivatives with increased proteolytic stability and high receptor selectivity. Stabilizing motifs, including lactamization and lipidation, were evaluated regarding AM1 R and CGRPR activation. Furthermore, the central DKDK motif of the peptide was replaced by oligoethylene glycol linkers. The modified peptides were synthesized by Fmoc/t-Bu solid-phase peptide synthesis and receptor activation of AM1 R and CGRPR was measured by cAMP reporter gene assay. Peptide stability was tested in human blood plasma and porcine liver homogenate and analyzed by RP-HPLC and MALDI-ToF mass spectrometry. Combination of the favorable lactam, lipidation, ethylene glycol linker, and previously described disulfide mimetic resulted in highly stabilized analogs with a plasma half-life of more than 144 h. The compounds display excellent AM1 R activity and wild-type-like selectivity toward CGRPR. Additionally, dose-dependent vasodilatory effects of the ADM derivatives lasted for several hours in rodents. Thus, we successfully developed an ADM analog with long-term in vivo activity.
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Affiliation(s)
- Eva-Maria Jülke
- Institute of Biochemistry, Faculty of Life Sciences, Leipzig University, Leipzig, Germany
| | - Jan-Patrick Fischer
- Institute of Biochemistry, Faculty of Life Sciences, Leipzig University, Leipzig, Germany
| | - Sylvia Els-Heindl
- Institute of Biochemistry, Faculty of Life Sciences, Leipzig University, Leipzig, Germany
| | - Donald Bierer
- Division Pharmaceuticals, Drug Discovery Sciences, Bayer AG, Wuppertal, Germany
| | - Ingo Flamme
- Division Pharmaceuticals, Research & Early Development, Bayer AG, Wuppertal, Germany
| | - Johannes Köbberling
- Division Pharmaceuticals, Drug Discovery Sciences, Bayer AG, Wuppertal, Germany
| | - Bernd Riedl
- Division Pharmaceuticals, Drug Discovery Sciences, Bayer AG, Wuppertal, Germany
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Chang CL, Cai Z, Hsu SYT. Sustained Activation of CLR/RAMP Receptors by Gel-Forming Agonists. Int J Mol Sci 2022; 23:ijms232113408. [PMID: 36362188 PMCID: PMC9655119 DOI: 10.3390/ijms232113408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/30/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022] Open
Abstract
Background: Adrenomedullin (ADM), adrenomedullin 2 (ADM2), and CGRP family peptides are important regulators of vascular vasotone and integrity, neurotransmission, and fetoplacental development. These peptides signal through CLR/RAMP1, 2, and 3 receptors, and protect against endothelial dysfunction in disease models. As such, CLR/RAMP receptor agonists are considered important therapeutic candidates for various diseases. Methods and Results: Based on the screening of a series of palmitoylated chimeric ADM/ADM2 analogs, we demonstrated a combination of lipidation and accommodating motifs at the hinge region of select peptides is important for gaining an enhanced receptor-activation activity and improved stimulatory effects on the proliferation and survival of human lymphatic endothelial cells when compared to wild-type peptides. In addition, by serendipity, we found that select palmitoylated analogs self-assemble to form liquid gels, and subcutaneous administration of an analog gel led to the sustained presence of the peptide in the circulation for >2 days. Consistently, subcutaneous injection of the analog gel significantly reduced the blood pressure in SHR rats and increased vasodilation in the hindlimbs of adult rats for days. Conclusions: Together, these data suggest gel-forming adrenomedullin analogs may represent promising candidates for the treatment of various life-threatening endothelial dysfunction-associated diseases such as treatment-resistant hypertension and preeclampsia, which are in urgent need of an effective drug.
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Affiliation(s)
- Chia Lin Chang
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Kweishan, Taoyuan 20878, Taiwan
| | - Zheqing Cai
- CL Laboratory LLC, Gaithersburg, MD 20878, USA
| | - Sheau Yu Teddy Hsu
- Adepthera LLC, San Jose, CA 95138, USA
- Correspondence: ; Tel.: +1-650-799-3496
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Santos-Gomes J, Gandra I, Adão R, Perros F, Brás-Silva C. An Overview of Circulating Pulmonary Arterial Hypertension Biomarkers. Front Cardiovasc Med 2022; 9:924873. [PMID: 35911521 PMCID: PMC9333554 DOI: 10.3389/fcvm.2022.924873] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 06/21/2022] [Indexed: 11/16/2022] Open
Abstract
Pulmonary arterial hypertension (PAH), also known as Group 1 Pulmonary Hypertension (PH), is a PH subset characterized by pulmonary vascular remodeling and pulmonary arterial obstruction. PAH has an estimated incidence of 15-50 people per million in the United States and Europe, and is associated with high mortality and morbidity, with patients' survival time after diagnosis being only 2.8 years. According to current guidelines, right heart catheterization is the gold standard for diagnostic and prognostic evaluation of PAH patients. However, this technique is highly invasive, so it is not used in routine clinical practice or patient follow-up. Thereby, it is essential to find new non-invasive strategies for evaluating disease progression. Biomarkers can be an effective solution for determining PAH patient prognosis and response to therapy, and aiding in diagnostic efforts, so long as their detection is non-invasive, easy, and objective. This review aims to clarify and describe some of the potential new candidates as circulating biomarkers of PAH.
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Affiliation(s)
- Joana Santos-Gomes
- UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Inês Gandra
- UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Rui Adão
- UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Frédéric Perros
- Paris-Porto Pulmonary Hypertension Collaborative Laboratory (3PH), UMR_S 999, INSERM, Université Paris-Saclay, Paris, France
- Université Paris–Saclay, AP-HP, INSERM UMR_S 999, Service de Pneumologie et Soins Intensifs Respiratoires, Hôpital de Bicêtre, Le Kremlin Bicêtre, France
| | - Carmen Brás-Silva
- UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
- Faculty of Nutrition and Food Sciences, University of Porto, Porto, Portugal
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Fischer JP, Els-Heindl S, Beck-Sickinger AG. Adrenomedullin - Current perspective on a peptide hormone with significant therapeutic potential. Peptides 2020; 131:170347. [PMID: 32569606 DOI: 10.1016/j.peptides.2020.170347] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Revised: 06/04/2020] [Accepted: 06/08/2020] [Indexed: 12/11/2022]
Abstract
The peptide hormone adrenomedullin (ADM) consists of 52 amino acids and plays a pivotal role in the regulation of many physiological processes, particularly those of the cardiovascular and lymphatic system. Like calcitonin (CT), calcitonin gene-related peptide (CGRP), intermedin (IMD) and amylin (AMY), it belongs to the CT/CGRP family of peptide hormones, which despite their low little sequence identity share certain characteristic structural features as well as a complex multicomponent receptor system. ADM, IMD and CGRP exert their biological effects by activation of the calcitonin receptor-like receptor (CLR) as a complex with one of three receptor activity-modifying proteins (RAMP), which alter the ligand affinity. Selectivity within the receptor system is largely mediated by the amidated C-terminus of the peptide hormones, which bind to the extracellular domains of the receptors. This enables their N-terminus consisting of a disulfide-bonded ring structure and a helical segment to bind within the transmembrane region and to induce an active receptor confirmation. ADM is expressed in a variety of tissues in the human body and is fundamentally involved in multitude biological processes. Thus, it is of interest as a diagnostic marker and a promising candidate for therapeutic interventions. In order to fully exploit the potential of ADM, it is necessary to improve its pharmacological profile by increasing the metabolic stability and, ideally, creating receptor subtype-selective analogs. While several successful attempts to prolong the half-life of ADM were recently reported, improving or even retaining receptor selectivity remains challenging.
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Affiliation(s)
- Jan-Patrick Fischer
- Institut für Biochemie, Universität Leipzig, Brüderstraße 34, 04103 Leipzig, Germany
| | - Sylvia Els-Heindl
- Institut für Biochemie, Universität Leipzig, Brüderstraße 34, 04103 Leipzig, Germany
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Tellİ G, Tel BC, GÜmÜŞel B. The Cardiopulmonary Effects of the Calcitonin Gene-related Peptide Family. Turk J Pharm Sci 2020; 17:349-356. [PMID: 32636714 DOI: 10.4274/tjps.galenos.2019.47123] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 06/27/2019] [Indexed: 01/12/2023]
Abstract
Cardiopulmonary diseases are very common among the population. They are high-cost diseases and there are still no definitive treatments. The roles of members of the calcitonin-gene related-peptide (CGRP) family in treating cardiopulmonary diseases have been studied for many years and promising results obtained. Especially in recent years, two important members of the family, adrenomedullin and adrenomedullin2/intermedin, have been considered new treatment targets in cardiopulmonary diseases. In this review, the roles of CGRP family members in cardiopulmonary diseases are investigated based on the studies performed to date.
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Affiliation(s)
- Gökçen Tellİ
- Hacettepe University Faculty of Pharmacy, Department of Pharmacology, Ankara, Turkey
| | - Banu Cahide Tel
- Hacettepe University Faculty of Pharmacy, Department of Pharmacology, Ankara, Turkey
| | - Bülent GÜmÜŞel
- Lokman Hekim University Faculty of Pharmacy, Department of Pharmacology, Ankara, Turkey
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7
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Midregional proadrenomedullin predicts reduced blood pressure and glucose elevation over time despite enhanced progression of obesity markers. J Hypertens 2020; 37:590-595. [PMID: 30540625 DOI: 10.1097/hjh.0000000000001893] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
OBJECTIVES Elevated plasma levels of the vasodilating hormone adrenomedullin (ADM) predict cardiovascular disease and have been associated with hypertension and obesity. We aimed to examine the independent relationship between ADM and the progression of major cardiometabolic risk factors during long-term follow-up. METHODS We studied midregional pro-ADM (MR-proADM) in fasting plasma in 3298 participants from the population-based Malmö Diet and Cancer Study - Cardiovascular Cohort, re-examined after 17 years of follow-up and related baseline MR-proADM to cardiometabolic risk factors cross-sectionally and longitudinally. RESULTS At baseline, after full adjustment, each SD increment of MR-proADM was independently related to (beta ± standard error, P value) higher SBP (0.956 ± 0.319 mmHg, P = 0.003), BMI (0.912 ± 0.061 kg/m, P = 1.42 × 10), waist (2.28 ± 0.158 cm, P = 8.46 × 10) and fasting blood glucose (0.046 ± 0.018 mmol/l, P = 0.01). After full adjustment, including the baseline level of the risk factor whose degree of progression was studied, each SD increment of MR-proADM predicted significantly reduced progression of SBP (-1.170 ± 0.337 mmHg, P = 0.001) and fasting blood glucose (-0.055 ± 0.023 mmol/l, P = 0.015), but greater increase of BMI (0.101 ± 0.051 kg/m, P = 0.047) and waist (0.600 ± 0.144 cm, P = 3.1 × 10). CONCLUSION Despite cross-sectional associations with higher levels of blood pressure and glucose, high levels of MR-proADM predict a slower progression of blood pressure and glycemia during long-term follow-up. Conversely, the cross-sectional associations with higher levels of MR-proADM and obesity were paralleled by a faster progression of obesity markers over time. These results may be important for assessment of long-term effects of therapies modulating levels of ADM.
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Keshavarz A, Kadry H, Alobaida A, Ahsan F. Newer approaches and novel drugs for inhalational therapy for pulmonary arterial hypertension. Expert Opin Drug Deliv 2020; 17:439-461. [PMID: 32070157 DOI: 10.1080/17425247.2020.1729119] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by remodeling of small pulmonary arteries leading to increased pulmonary arterial pressure. Existing treatments acts to normalize vascular tone via three signaling pathways: the prostacyclin, the endothelin-1, and the nitric oxide. Although over the past 20 years, there has been considerable progress in terms of treatments for PAH, the disease still remains incurable with a disappointing prognosis.Areas covered: This review summarizes the pathophysiology of PAH, the advantages and disadvantages of the inhalation route, and assess the relative advantages various inhaled therapies for PAH. The recent studies concerning the development of controlled-release drug delivery systems loaded with available anti-PAH drugs have also been summarized.Expert opinion: The main obstacles of current pharmacotherapies of PAH are their short half-life, stability, and formulations, resulting in reducing the efficacy and increasing systemic side effects and unknown pathogenesis of PAH. The pulmonary route has been proposed for delivering anti-PAH drugs to overcome the shortcomings. However, the application of approved inhaled anti-PAH drugs is limited. Inhalational delivery of controlled-release nanoformulations can overcome these restrictions. Extensive studies are required to develop safe and effective drug delivery systems for PAH patients.
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Affiliation(s)
- Ali Keshavarz
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA
| | - Hossam Kadry
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA
| | - Ahmed Alobaida
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA
| | - Fakhrul Ahsan
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA
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Lionetto L, Curto M, Cisale GY, Capi M, Cipolla F, Guglielmetti M, Martelletti P. Fremanezumab for the preventive treatment of migraine in adults. Expert Rev Clin Pharmacol 2019; 12:741-748. [PMID: 31220963 DOI: 10.1080/17512433.2019.1635452] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Introduction: The Calcitonin Gene-Related Peptide (CGRP) has been implicated in migraine pathophysiology due to its role in neurogenic inflammation and transmission of trigeminovascular nociceptive signal. New molecules targeting CGRP and its receptor have been developed as migraine-specific preventative treatments. Fremanezumab (or TEV-48,125, LBR-101), a human monoclonal antibody against CGRP, has been recently approved for clinical use by FDA and EMA. Areas covered: This paper briefly discusses the calcitonin family of neurotransmitters and resultant activation pathways and in-depth the chemical properties, pharmacodynamics, pharmacokinetics, clinical efficacy and safety of Fremanezumab for the prophylactic treatment of migraine. Expert opinion: Fremanezumab, a migraine-specific drug, is effective and safe as a prophylactic treatment of chronic and episodic migraine. As a monoclonal antibody, it was not associated to liver toxicity and is not expected to interact with other drugs. The long half-life might improve patients' compliance. Long-term effects of CGRP block in cardiovascular, grastrointestinal and bone functions should be evaluated in ongoing trials, since CGRP is involved in multiple biological activities in the human body. Nevertheless, targeting CGRP itself allows the receptor binding with other ligands involved in several physiological functions. Thus, the long-term treatment with Fremanezumab is expected to be associated with a lower risk of severe adverse effects.
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Affiliation(s)
- Luana Lionetto
- a Mass Spectrometry Laboratory Unit, Sant'Andrea University Hospital , Rome , Italy
| | - Martina Curto
- b Department of Human Neurosciences, Sapienza University of Rome , Rome , Italy.,c International Mood & Psychotic Disorders Research Consortium, Mailman Research Center , Belmont , MA , USA.,d Department of Mental Health , Colleferro (RM) , Italy
| | - Giusy Ylenia Cisale
- e Department of Physiology and Pharmacology, Sapienza University , Rome , Italy
| | - Matilde Capi
- a Mass Spectrometry Laboratory Unit, Sant'Andrea University Hospital , Rome , Italy
| | - Fabiola Cipolla
- f Department of Clinical and Molecular Medicine, Sapienza University of Rome , Rome , Italy
| | - Martina Guglielmetti
- g Department of Medical, Surgical and Experimental Sciences, University of Sassari , Sassari , Italy.,h Regional Referral Headache Center, Sant'Andrea University Hospital , Rome , Italy
| | - Paolo Martelletti
- f Department of Clinical and Molecular Medicine, Sapienza University of Rome , Rome , Italy.,h Regional Referral Headache Center, Sant'Andrea University Hospital , Rome , Italy
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Telli G, Tel BC, Yersal N, Korkusuz P, Gumusel B. Effect of intermedin/adrenomedullin2 on the pulmonary vascular bed in hypoxia-induced pulmonary hypertensive rats. Life Sci 2018; 192:62-67. [DOI: 10.1016/j.lfs.2017.11.031] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 11/14/2017] [Accepted: 11/17/2017] [Indexed: 10/18/2022]
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Schönauer R, Els-Heindl S, Beck-Sickinger AG. Adrenomedullin - new perspectives of a potent peptide hormone. J Pept Sci 2017; 23:472-485. [DOI: 10.1002/psc.2953] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 11/24/2016] [Accepted: 11/28/2016] [Indexed: 12/14/2022]
Affiliation(s)
- Ria Schönauer
- Faculty of Biosciences, Pharmacy and Psychology, Institute of Biochemistry; Leipzig University; Brüderstraße 34 04103 Leipzig Germany
| | - Sylvia Els-Heindl
- Faculty of Biosciences, Pharmacy and Psychology, Institute of Biochemistry; Leipzig University; Brüderstraße 34 04103 Leipzig Germany
| | - Annette G. Beck-Sickinger
- Faculty of Biosciences, Pharmacy and Psychology, Institute of Biochemistry; Leipzig University; Brüderstraße 34 04103 Leipzig Germany
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12
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Su JB. Vascular endothelial dysfunction and pharmacological treatment. World J Cardiol 2015; 7:719-741. [PMID: 26635921 PMCID: PMC4660468 DOI: 10.4330/wjc.v7.i11.719] [Citation(s) in RCA: 145] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 06/23/2015] [Accepted: 09/18/2015] [Indexed: 02/06/2023] Open
Abstract
The endothelium exerts multiple actions involving regulation of vascular permeability and tone, coagulation and fibrinolysis, inflammatory and immunological reactions and cell growth. Alterations of one or more such actions may cause vascular endothelial dysfunction. Different risk factors such as hypercholesterolemia, homocystinemia, hyperglycemia, hypertension, smoking, inflammation, and aging contribute to the development of endothelial dysfunction. Mechanisms underlying endothelial dysfunction are multiple, including impaired endothelium-derived vasodilators, enhanced endothelium-derived vasoconstrictors, over production of reactive oxygen species and reactive nitrogen species, activation of inflammatory and immune reactions, and imbalance of coagulation and fibrinolysis. Endothelial dysfunction occurs in many cardiovascular diseases, which involves different mechanisms, depending on specific risk factors affecting the disease. Among these mechanisms, a reduction in nitric oxide (NO) bioavailability plays a central role in the development of endothelial dysfunction because NO exerts diverse physiological actions, including vasodilation, anti-inflammation, antiplatelet, antiproliferation and antimigration. Experimental and clinical studies have demonstrated that a variety of currently used or investigational drugs, such as angiotensin-converting enzyme inhibitors, angiotensin AT1 receptors blockers, angiotensin-(1-7), antioxidants, beta-blockers, calcium channel blockers, endothelial NO synthase enhancers, phosphodiesterase 5 inhibitors, sphingosine-1-phosphate and statins, exert endothelial protective effects. Due to the difference in mechanisms of action, these drugs need to be used according to specific mechanisms underlying endothelial dysfunction of the disease.
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Mishra A, Mohammad G, Norboo T, Newman JH, Pasha MAQ. Lungs at high-altitude: genomic insights into hypoxic responses. J Appl Physiol (1985) 2015; 119:1-15. [DOI: 10.1152/japplphysiol.00513.2014] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Accepted: 04/20/2015] [Indexed: 11/22/2022] Open
Abstract
Hypobaric hypoxia at high altitude (HA) results in reduced blood arterial oxygen saturation, perfusion of organs with hypoxemic blood, and direct hypoxia of lung tissues. The pulmonary complications in the cells of the pulmonary arterioles due to hypobaric hypoxia are the basis of the pathophysiological mechanisms of high-altitude pulmonary edema (HAPE). Some populations that have dwelled at HA for thousands of years have evolutionarily adapted to this environmental stress; unadapted populations may react with excessive physiological responses that impair health. Individual variations in response to hypoxia and the mechanisms of HA adaptation provide insight into physiological responses. Adaptive and maladaptive responses include alterations in pathways such as oxygen sensing, hypoxia signaling, K+- and Ca2+-gated channels, redox balance, and the renin-angiotensin-aldosterone system. Physiological imbalances are linked with genetic susceptibilities, and nonhomeostatic responses in gene regulation that occur by small RNAs, histone modification, and DNA methylation predispose susceptible humans to these HA illnesses. Elucidation of the interaction of these factors will lead to a more comprehensive understanding of HA adaptations and maladaptations and will lead to new therapeutics for HA disorders related to hypoxic lungs.
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Affiliation(s)
- Aastha Mishra
- Department of Genomics and Molecular Medicine, Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, Delhi, India
- Department of Biotechnology, University of Pune, Pune, India
| | - Ghulam Mohammad
- Department of Medicine, SNM Hospital, Leh, Ladakh, J&K, India
| | - Tsering Norboo
- Ladakh Institute of Prevention, Leh, Ladakh, J&K, India; and
| | - John H. Newman
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - M. A. Qadar Pasha
- Department of Genomics and Molecular Medicine, Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, Delhi, India
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14
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Endothelial progenitor cells and pulmonary arterial hypertension. Heart Lung Circ 2014; 23:595-601. [PMID: 24680485 DOI: 10.1016/j.hlc.2014.02.007] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2014] [Accepted: 02/17/2014] [Indexed: 01/23/2023]
Abstract
Pulmonary arterial hypertension (PAH) is a progressive disease characterised by lung endothelial cell dysfunction and vascular remodelling. A number of studies now suggest that endothelial progenitor cells (EPCs) may induce neovascularisation and could be a promising approach for cell based therapy for PAH. On the contrary EPCs may contribute to pulmonary vascular remodelling, particularly in end-stage pulmonary disease. This review article will provide a brief summary of the relationship between PAH and EPCs, the application of the EPCs to PAH and highlight the potential clinical application of the EPCs cell therapy to PAH.
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Morrell NW, Archer SL, Defelice A, Evans S, Fiszman M, Martin T, Saulnier M, Rabinovitch M, Schermuly R, Stewart D, Truebel H, Walker G, Stenmark KR. Anticipated classes of new medications and molecular targets for pulmonary arterial hypertension. Pulm Circ 2013; 3:226-44. [PMID: 23662201 PMCID: PMC3641734 DOI: 10.4103/2045-8932.109940] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) remains a life-limiting condition with a major impact on the ability to lead a normal life. Although existing therapies may improve the outlook in some patients there remains a major unmet need to develop more effective therapies in this condition. There have been significant advances in our understanding of the genetic, cell and molecular basis of PAH over the last few years. This research has identified important new targets that could be explored as potential therapies for PAH. In this review we discuss whether further exploitation of vasoactive agents could bring additional benefits over existing approaches. Approaches to enhance smooth muscle cell apotosis and the potential of receptor tyrosine kinase inhibition are summarised. We evaluate the role of inflammation, epigenetic changes and altered glycolytic metabolism as potential targets for therapy, and whether inherited genetic mutations in PAH have revealed druggable targets. The potential of cell based therapies and gene therapy are also discussed. Potential candidate pathways that could be explored in the context of experimental medicine are identified.
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16
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Kim KC, Lee HR, Kim SJ, Cho MS, Hong YM. Changes of gene expression after bone marrow cell transfusion in rats with monocrotaline-induced pulmonary hypertension. J Korean Med Sci 2012; 27:605-13. [PMID: 22690090 PMCID: PMC3369445 DOI: 10.3346/jkms.2012.27.6.605] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2011] [Accepted: 03/28/2012] [Indexed: 12/23/2022] Open
Abstract
Pulmonary artery hypertension (PAH) causes right ventricular failure and possibly even death by a progressive increase in pulmonary vascular resistance. Bone marrow-derived mesenchymal stem cell therapy has provided an alternative treatment for ailments of various organs by promoting cell regeneration at the site of pathology. The purpose of this study was to investigate changes of pulmonary haemodynamics, pathology and expressions of various genes, including ET (endothelin)-1, ET receptor A (ERA), endothelial nitric oxide synthase (NOS) 3, matrix metalloproteinase (MMP) 2, tissue inhibitor of matrix metalloproteinase (TIMP), interleukin (IL)-6 and tumor necrosis factor (TNF)-α in monocrotaline (MCT)-induced PAH rat models after bone marrow cell (BMC) transfusion. The rats were grouped as the control (C) group, monocrotaline (M) group, and BMC transfusion (B) group. M and B groups received subcutaneous (sc) injection of MCT (60 mg/kg). BMCs were transfused by intravenous injection at the tail 1 week after MCT injection in B group. Results showed that the average RV pressure significantly decreased in the B group compared with the M group. RV weight and the ratio of RH/LH+septum significantly decreased in the B group compared to the M group. Gene expressions of ET-1, ERA, NOS 3, MMP 2, TIMP, IL-6, and TNF-α significantly decreased in week 4 in the B group compared with the M group. In conclusion, BMC transfusion appears to improve survival rate, RVH, and mean RV pressure, and decreases gene expressions of ET-1, ERA, NOS 3, MMP 2, TIMP, IL-6, and TNF-α.
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Affiliation(s)
- Kwan Chang Kim
- Department of Thoracic and Cardiovascular Surgery, Ewha Womans University, Seoul, Korea
| | - Hae Ryun Lee
- Department of Pediatrics, Ewha Womans University, Seoul, Korea
| | - Sung Jin Kim
- Department of Pediatrics, Ewha Womans University, Seoul, Korea
| | - Min-Sun Cho
- Department of Pathology, Ewha Womans University, Seoul, Korea
| | - Young Mi Hong
- Department of Pediatrics, Ewha Womans University, Seoul, Korea
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17
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Abstract
Current treatment of pulmonary arterial hypertension, which includes the use of prostacyclins, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors, either alone or in combination, often leads to improvements in functional capacity and modest decreases in pulmonary artery pressure. Disappointingly, however, two recent meta-analysis reviewing the controlled trials in pulmonary arterial hypertension, using these three agents, demonstrated little or no increase in survival. Importantly, however, increasing knowledge of the cellular and molecular basis of pulmonary arterial hypertension has led to the development of new agents aimed at either reversing sustained vasoconstriction or stopping/reversing the abnormal cell and extracellular matrix accumulation that, in combination, obstruct pulmonary blood flow and ultimately cause right heart failure. Rho kinase inhibitors, vasodilator peptides (such as vasoactive intestinal peptide and adrenomedullin), and endothelial nitric oxide synthase coupling agents (cicletanine) have been shown sometimes to exert potent pulmonary vasodilatory effects in animal models and in pilot studies in humans. Tyrosine kinase inhibitors (platelet-derived growth factor and epidermal growth factor receptor inhibitors), multikinase inhibitors (tyrosine kinase and serine/threonine kinase), elastase inhibitors, metabolic modulators (e.g., dichloroacetate), survivin inhibitors, and HMG-COA reductase inhibitors have been shown to reverse pulmonary hypertension in rodent models of pulmonary hypertension through inhibition of cell proliferation and induction of apoptosis. Early success in human pulmonary arterial hypertension with tyrosine kinase inhibitors has appeared in case reports. Furthermore, anti-inflammatory/immunomodulatory agents (thiazolidinedinones, rapamycin, cyclosporine, and STAT3 inhibitors) have been demonstrated to be effective at reducing vascular remodeling in animal models. Collectively, these studies are exciting and open potential new avenues for treatment. Caution should be exercised, however, as many agents, which are successful at preventing or reversing pulmonary arterial hypertension in currently used animal models, do not result in similar long-term success in the treatment of human pulmonary arterial hypertension.
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18
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Rubin LJ. Treatment of Pulmonary Arterial Hypertension Due to Scleroderma: Challenges for the Future. Rheum Dis Clin North Am 2008; 34:191-7; viii. [DOI: 10.1016/j.rdc.2007.11.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Xu Y, Krukoff TL. Adrenomedullin in the rostral ventrolateral medulla inhibits baroreflex control of heart rate: a role for protein kinase A. Br J Pharmacol 2007; 148:70-7. [PMID: 16501581 PMCID: PMC1617038 DOI: 10.1038/sj.bjp.0706698] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
1 The rostral ventrolateral medulla (RVLM) is an essential vasomotor center in the brainstem which participates in maintaining resting levels of arterial pressure and for regulating baroreflex activity. We have demonstrated that microinjections of adrenomedullin (ADM), a vasoactive neuropeptide, into the RVLM cause increased resting mean arterial pressure (MAP) and heart rate (HR). However, the effect of ADM on baroreflex function remains unclear. 2 The purposes of the present study were to investigate the effect of ADM in the RVLM on the regulation of baroreflex activity and to identify the underlying mechanisms. Baroreflex curves were generated with intravenous injections of multiple doses of phenylephrine and nitroprusside. The upper and lower plateaus, reflex range, MAP at the midpoint of HR range (MAP(50)), and gain were evaluated before and after various microinjections were made into the RVLM of urethane-anesthetized rats. 3 Microinjections of ADM decreased the upper plateau, reflex range, and gain, and increased MAP(50), indicating that ADM in the RVLM impairs baroreflex function. 4 ADM(22-52), a putative ADM receptor antagonist, significantly increased the baroreflex gain and upper plateau, demonstrating that endogenous ADM tonically inhibits the baroreflex. Coinjections of ADM(22-52) with ADM blocked the ADM-induced baroreflex responses. 5 ADM's effect was abolished with H-89, a protein kinase A (PKA) inhibitor. 6 Our results show that ADM in the RVLM exerts an inhibitory effect on baroreflex activity via an ADM receptor-mediated mechanism, and that activation of PKA is involved in this event.
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Affiliation(s)
- Yong Xu
- Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada T6G 2H7.
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20
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O'Callaghan DS, O'Callaghan D, Gaine SP. Combination therapy and new types of agents for pulmonary arterial hypertension. Clin Chest Med 2007; 28:169-85, ix. [PMID: 17338934 DOI: 10.1016/j.ccm.2006.11.011] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
This review assesses the available evidence supporting the use of drug combinations for the management of the various forms of pulmonary arterial hypertension (PAH). Ongoing and forthcoming randomized trials evaluating this strategy are also highlighted. Furthermore, new types of agents to treat PAH in the future are explored.
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Affiliation(s)
- Dermot S O'Callaghan
- Department of Respiratory Medicine, Mater Misericordiae University Hospital, University College Dublin, Eccles Street, Dublin 7, Ireland
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21
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Baber SR, Deng W, Master RG, Bunnell BA, Taylor BK, Murthy SN, Hyman AL, Kadowitz PJ. Intratracheal mesenchymal stem cell administration attenuates monocrotaline-induced pulmonary hypertension and endothelial dysfunction. Am J Physiol Heart Circ Physiol 2007; 292:H1120-8. [PMID: 16980338 DOI: 10.1152/ajpheart.00173.2006] [Citation(s) in RCA: 140] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The administration of mesenchymal stem cells (MSCs) has been proposed for the treatment of pulmonary hypertension. However, the effect of intratracheally administered MSCs on the pulmonary vascular bed in monocrotaline-treated rats has not been determined. In the present study, the effect of intratracheal administration of rat MSCs (rMSCs) on monocrotaline-induced pulmonary hypertension and impaired endothelium-dependent responses were investigated in the rat. Intravenous injection of monocrotaline increased pulmonary arterial pressure and vascular resistance and decreased pulmonary vascular responses to acetylcholine without altering responses to sodium nitroprusside and without altering systemic responses to the vasodilator agents when responses were evaluated at 5 wk. The intratracheal injection of 3 × 106rMSCs 2 wk after administration of monocrotaline attenuated the rise in pulmonary arterial pressure and pulmonary vascular resistance and restored pulmonary responses to acetylcholine toward values measured in control rats. Treatment with rMSCs decreased the right ventricular hypertrophy induced by monocrotaline. Immunohistochemical studies showed widespread distribution of lacZ-labeled rMSCs in lung parenchyma surrounding airways in monocrotaline-treated rats. Immunofluorescence studies revealed that transplanted rMSCs retained expression of von Willebrand factor and smooth muscle actin markers specific for endothelial and smooth muscle phenotypes. However, immunolabeled cells were not detected in the wall of pulmonary vessels. These data suggest that the decrease in pulmonary vascular resistance and improvement in response to acetylcholine an endothelium-dependent vasodilator in monocrotaline-treated rats may result from a paracrine effect of the transplanted rMSCs in lung parenchyma, which improves vascular endothelial function in the monocrotaline-injured lung.
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MESH Headings
- Acetylcholine/pharmacology
- Animals
- Blood Pressure/drug effects
- Cell Differentiation
- Cells, Cultured
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Endothelium, Vascular/drug effects
- Endothelium, Vascular/physiopathology
- Hypertension, Pulmonary/chemically induced
- Hypertension, Pulmonary/physiopathology
- Hypertension, Pulmonary/surgery
- Hypertrophy, Right Ventricular/physiopathology
- Hypertrophy, Right Ventricular/prevention & control
- Lung/blood supply
- Lung/pathology
- Male
- Mesenchymal Stem Cell Transplantation/methods
- Mesenchymal Stem Cells/cytology
- Monocrotaline
- Paracrine Communication
- Phenotype
- Pulmonary Circulation/drug effects
- Rats
- Rats, Sprague-Dawley
- Time Factors
- Trachea/surgery
- Vascular Resistance
- Vasodilation/drug effects
- Vasodilator Agents/pharmacology
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Affiliation(s)
- Syed R Baber
- Department of Pharmacology SL83, Tulane University Health Sciences Center, 1430 Tulane Ave., New Orleans, LA 70112, USA
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22
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Hobara N, Goda M, Kitamura Y, Sendou T, Gomita Y, Kawasaki H. Adrenomedullin facilitates reinnervation of phenol-injured perivascular nerves in the rat mesenteric resistance artery. Neuroscience 2007; 144:721-30. [PMID: 17101235 DOI: 10.1016/j.neuroscience.2006.09.031] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2006] [Revised: 09/18/2006] [Accepted: 09/20/2006] [Indexed: 11/20/2022]
Abstract
Our previous report showed that innervation of calcitonin gene-related peptide (CGRP)- and neuropeptide Y (NPY)-containing nerves in rat mesenteric resistance arteries was markedly reduced by topical application of phenol, and that nerve growth factor (NGF) facilitates the reinnervation of both nerves. We also demonstrated that a CGRP superfamily peptide, adrenomedullin, is distributed in perivascular nerves of rat mesenteric resistance arteries. In the present study, we investigated the influence of adrenomedullin on the reinnervation of mesenteric perivascular nerves following topical phenol treatment. Under pentobarbital-Na anesthesia, 8-week-old Wistar rats underwent in vivo topical application of phenol (10% phenol in 90% ethanol) to the superior mesenteric artery proximal to the bifurcation of the abdominal aorta. After the treatment, the animals were subjected to immunohistochemistry of the third branch of small arteries proximal to the intestine and to vascular responsiveness testing on day 7. Topical phenol treatment caused marked reduction of the density of NPY-like immunoreactive (LI)- and CGRP-LI nerve fibers in the arteries. Adrenomedullin (360 or 1000 ng/h) or NGF (250 ng/h), which was administered intraperitoneally for 7 days using an osmotic mini-pump immediately after topical phenol treatment, significantly increased the density of CGRP-LI- and NPY-LI nerve fibers compared with saline. Treatment with adrenomedullin (1000 ng/h) or NGF restored adrenergic nerve-mediated vasoconstriction and CGRP nerve-mediated vasodilation in the perfused mesenteric artery treated topically with phenol. These results suggest that adrenomedullin, like NGF, has a facilitatory effect on the reinnervation of perivascular nerves.
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Affiliation(s)
- N Hobara
- Department of Clinical Pharmaceutical Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-Naka, Okayama, Japan
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23
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Abstract
Pulmonary hypertension (PH), defined as a mean pulmonary arterial (PA) pressure of >25 mmHg at rest or >30 mmHg during exercise, is characterized by a progressive and sustained increase in pulmonary vascular resistance that eventually leads to right ventricular failure. Clinically, PH may result from a variety of underlying diseases (Table 1 and Refs. 50, 113, 124). Pulmonary arterial hypertension (PAH) may be familial (FPAH) or sporadic (idiopathic, IPAH), formerly known as primary pulmonary hypertension, i.e., for which there is no demonstrable cause. More often, PAH is due to a variety of identifiable diseases including scleroderma and other collagen disorders, liver disease, human immunodeficiency virus, and the intake of appetite-suppressant drugs such as phentermine and fenfluramine (72). Other, more common, causes of PAH include left ventricular failure (perhaps the most common cause), valvular lesions, chronic pulmonary diseases, sleep-disordered breathing, and prolonged residence at high altitude. This classification, now widely accepted, was first proposed at a meeting in Evian, France, in 1998, and modified in Venice, Italy, in 2003 (124).
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Affiliation(s)
- Sami I Said
- Department of Medicine, State University of New York at Stony Brook, and Northport Veterans Affairs Medical Center, Stony Brook, NY 11794-8172, USA.
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24
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Yanagawa B, Nagaya N. Adrenomedullin: molecular mechanisms and its role in cardiac disease. Amino Acids 2006; 32:157-64. [PMID: 16583314 DOI: 10.1007/s00726-005-0279-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2005] [Accepted: 12/03/2005] [Indexed: 10/24/2022]
Abstract
Adrenomedullin (AM) is a potent, long-lasting vasoactive peptide originally isolated from human pheochromocytoma. Since its discovery, serum and tissue AM expression have been shown to be increased in experimental models and in patients with cardiac hypertrophy, myocardial infarction and end-stage heart failure with several beneficial effects. Considerable evidence exists for a wide range of autocrine, paracrine and endocrine mechanisms for AM which include vasodilatory, anti-apoptotic, angiogenic, anti-fibrotic, natriuretic, diuretic and positive inotropic. Thus, through regulation of body fluid or direct cardiac mechanisms, AM has additive and beneficial effects in the context of heart disease. Notable molecular mechanisms of AM include cyclic adenosine monophosphate, guanosine-3',5'-monophosphate, PI3K/Akt and MAPK-ERK-mediated cascades. Given the endogenous and multifunctional nature of AM, we consider this molecule to have great potential in the treatment of cardiovascular diseases. In agreement, early experimental and preliminary clinical studies suggest that AM is a new and promising therapy for cardiovascular diseases.
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Affiliation(s)
- B Yanagawa
- Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, Osaka, Japan
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25
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Brell B, Hippenstiel S, Dávid I, Pries AR, Habazettl H, Schmeck B, Suttorp N, Temmesfeld-Wollbrück B. Adrenomedullin treatment abolishes ileal mucosal hypoperfusion induced by Staphylococcus aureus α-toxin—An intravital microscopic study on an isolated rat ileum. Crit Care Med 2005; 33:2810-016. [PMID: 16352964 DOI: 10.1097/01.ccm.0000190625.14268.09] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVE Disturbances of intestinal microcirculation associated with sepsis and septic shock result in diminished mucosal oxygenation. Tissue hypoxia as well as mediator formation may lead to intestinal mucosa dysfunction. As a consequence, bacteria and their products as well as gut-derived inflammatory mediators may further perpetuate septic and inflammatory events. Adrenomedullin is produced in the mucosa of the gastrointestinal tract and has been shown to improve survival in experimental sepsis. Using pore-forming Staphylococcus aureus alpha-toxin as a potent initiator of inflammatory reactions, we tested the hypothesis that exogenously added adrenomedullin improves ileal mucosal perfusion. DESIGN Prospective, experimental study. SETTING University laboratory. SUBJECTS Isolated perfused ileum from male Sprague-Dawley rats INTERVENTIONS Adrenomedullin treatment of S. aureus alpha-toxin infused ileum. MEASUREMENT AND MAIN RESULTS An infusion of alpha-toxin (0.05 microg/mL) induced a significant decrease of red blood cell velocity in villus terminal arterioles from 1.7 to 0.7 mm/sec assessed by intravital microscopy. This was accompanied by a significant reduction of mucosal hemoglobin oxygenation from 71.8% to 17.5% and impaired oxygen uptake. At constant bulk flow and oxygen delivery, these data indicate a redistribution of blood perfusion away from mucosa. Subsequent intervention with 0.1 microM adrenomedullin redistributed blood flow back toward the mucosa, causing an improvement of mucosal hemoglobin oxygenation and of organ oxygen uptake. CONCLUSION These data suggest that exogenously added adrenomedullin protects ileum mucosa by diminishing alpha-toxin-induced microcirculatory disturbances. Further investigations will have to clarify the therapeutic potential of adrenomedullin in sepsis-related gut dysfunction.
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Affiliation(s)
- Bernhard Brell
- Department of Internal Medicine/Infectious Diseases, Charité-University Medicine Berlin, Berlin, Germany
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26
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Ueda K, Teragawa H, Kimura M, Matsuda K, Higashi Y, Yamagata T, Oshima T, Yoshizumi M, Chayama K. Adrenomedullin causes coronary vasodilation in humans: effects of inhibition of nitric oxide synthesis. J Cardiovasc Pharmacol 2005; 46:534-539. [PMID: 16160609 DOI: 10.1097/01.fjc.0000179156.51985.db] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Experimental studies have shown that adrenomedullin (AM) causes vasodilation, in part, mediated by endothelium-derived nitric oxide (NO). However, it remains to be clarified how NO is involved in AM-induced coronary vasoreactivity in humans. We examined whether NO contributes to the vasodilatory effects of adrenomedullin on human coronary arteries. In 10 patients with angiographically normal coronary arteries, adrenomedullin (low dose: 1 ng/kg/min; high dose: 10 ng/kg/min) was infused into the left coronary ostium before and after an infusion of N-monomethyl-L-arginine (L-NMMA, 40 micromol/min for 5 min), an NO synthase inhibitor. Coronary diameter and coronary blood flow (CBF) were evaluated by quantitative angiography and Doppler flow velocity measurements. Changes in these parameters in response to adrenomedullin were expressed as percent changes from baseline values. Adrenomedullin at a high dose dilated coronary arteries (3.7+/-0.5%, P<0.001). Adrenomedullin increased the coronary blood flow at both doses (low: 55.7+/-13.9%, P<0.01; high: 48.8+/-9.8%, P<0.001). After the infusion of L-NMMA, adrenomedullin-induced coronary vasodilation and increase in coronary blood flow were attenuated. These findings suggest that adrenomedullin dilates human coronary arteries through an increase in NO production, at least in part.
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Affiliation(s)
- Kentaro Ueda
- Department of Medicine and Molecular Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
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27
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Fischer JA, Born W. Introductory notes. Old and new paradigms in the field of the calcitonin family of peptides. Peptides 2004; 25:2001-2. [PMID: 15501533 DOI: 10.1016/j.peptides.2004.08.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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