Editorial

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3 pages, 207 KiB

Open AccessEditorial

Cardiac Peptides—Current Physiology, Pathophysiology, Biochemistry, Molecular Biology, and Clinical Application

by Toshio Nishikimi and Johji Kato

Biology 2022, 11(2), 330; https://doi.org/10.3390/biology11020330 - 18 Feb 2022

Cited by 4 | Viewed by 1630

Abstract

The heart has long been considered a pumping organ, consisting of muscles [...] Full article

(This article belongs to the Special Issue Cardiac Peptides-Current Physiology, Pathophysiology, Biochemistry, Molecular Biology, and Clinical Application)

Research

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17 pages, 4443 KiB

Open AccessArticle

Corin Deficiency Alters Adipose Tissue Phenotype and Impairs Thermogenesis in Mice

by Xianrui Zhang, Wenguo Li, Tiantian Zhou, Meng Liu, Qingyu Wu and Ningzheng Dong

Biology 2022, 11(8), 1101; https://doi.org/10.3390/biology11081101 - 23 Jul 2022

Cited by 7 | Viewed by 1979

Abstract

Atrial natriuretic peptide (ANP) is a key regulator in body fluid balance and cardiovascular biology. In addition to its role in enhancing natriuresis and vasodilation, ANP increases lipolysis and thermogenesis in adipose tissue. Corin is a protease responsible for ANP activation. It remains [...] Read more.

Atrial natriuretic peptide (ANP) is a key regulator in body fluid balance and cardiovascular biology. In addition to its role in enhancing natriuresis and vasodilation, ANP increases lipolysis and thermogenesis in adipose tissue. Corin is a protease responsible for ANP activation. It remains unknown if corin has a role in regulating adipose tissue function. Here, we examined adipose tissue morphology and function in corin knockout (KO) mice. We observed increased weights and cell sizes in white adipose tissue (WAT), decreased levels of uncoupling protein 1 (Ucp1), a brown adipocyte marker in WAT and brown adipose tissue (BAT), and suppressed thermogenic gene expression in BAT from corin KO mice. At regular room temperature, corin KO and wild-type mice had similar metabolic rates. Upon cold exposure at 4 °C, corin KO mice exhibited impaired thermogenic responses and developed hypothermia. In BAT from corin KO mice, the signaling pathway of p38 mitogen-activated protein kinase, peroxisome proliferator-activated receptor c coactivator 1a, and Ucp1 was impaired. In cell culture, ANP treatment increased Ucp1 expression in BAT-derived adipocytes from corin KO mice. These data indicate that corin mediated-ANP activation is an important hormonal mechanism in regulating adipose tissue function and body temperature upon cold exposure in mice. Full article

(This article belongs to the Special Issue Cardiac Peptides-Current Physiology, Pathophysiology, Biochemistry, Molecular Biology, and Clinical Application)

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12 pages, 1828 KiB

Open AccessArticle

Development of Long-Acting Human Adrenomedullin Fc-Fusion Proteins

by Sayaka Nagata, Motoo Yamasaki, Nobuko Kuroishi and Kazuo Kitamura

Biology 2022, 11(7), 1074; https://doi.org/10.3390/biology11071074 - 19 Jul 2022

Cited by 4 | Viewed by 1351

Abstract

(1) Background: Human adrenomedullin (hAM) is a hypotensive peptide hormone that exerts powerful anti-inflammatory effects. AM also had therapeutic effects in various animal experimental models of disease. However, treatment required continuous administration as the half-life of native AM is short in blood. To [...] Read more.

(1) Background: Human adrenomedullin (hAM) is a hypotensive peptide hormone that exerts powerful anti-inflammatory effects. AM also had therapeutic effects in various animal experimental models of disease. However, treatment required continuous administration as the half-life of native AM is short in blood. To resolve this, we developed four human IgG1 and IgG4 Fc-fusion proteins containing full-length hAM or hAM residues 6-52. (2) Methods: We used mammalian cells to produce recombinant Fc-AM derivatives and tested the pharmacokinetics and biological activity of Fc-AM. (3) Results: We developed four Fc-fusion AMs (Fc-AM), which are long-acting AM derivatives in mammalian cells. Fc-AM had a prolonged half-life in blood and retained its ability to bind to the AM₁ receptor. Fc-AM (6-52) induced higher cAMP levels for the receptor than Fc-AM. After the administration of IgG1-AM (6-52) or IgG4-AM (6-52) to rats, tissue transfer to the kidney and small intestine was observed. In addition, treatment with IgG4-AM (6-52) inhibited blood pressure increase in spontaneously hypertensive rats. (4) Conclusions: Fc-AM produced from mammalian cells can be easily prepared and might be an effective novel therapeutic agent. Full article

(This article belongs to the Special Issue Cardiac Peptides-Current Physiology, Pathophysiology, Biochemistry, Molecular Biology, and Clinical Application)

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15 pages, 5304 KiB

Open AccessArticle

Endoglin and Activin Receptor-like Kinase 1 (Alk1) Modify Adrenomedullin Expression in an Organ-Specific Manner in Mice

by Josune García-Sanmartín, Judit Narro-Íñiguez, Alicia Rodríguez-Barbero and Alfredo Martínez

Biology 2022, 11(3), 358; https://doi.org/10.3390/biology11030358 - 24 Feb 2022

Cited by 4 | Viewed by 1859

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is a rare disease characterized by vascular malformations and profuse bleeding. The disease is caused by mutations in the components of the BMP-9 receptor: endoglin (ENG) and activin receptor-like kinase 1 (ACVRL1) genes. Recently, we [...] Read more.

Hereditary hemorrhagic telangiectasia (HHT) is a rare disease characterized by vascular malformations and profuse bleeding. The disease is caused by mutations in the components of the BMP-9 receptor: endoglin (ENG) and activin receptor-like kinase 1 (ACVRL1) genes. Recently, we reported that HHT patients expressed higher serum levels of adrenomedullin (AM) than healthy volunteers; thus, we studied the expression of AM (by enzyme immunoassay, qRT-PCR, immunohistochemistry, and Western blotting) in mice deficient in either one of the receptor components to investigate whether these defects may be the cause of that elevated AM in patients. We found that AM expression is not affected by these mutations in a consistent pattern. On the contrary, in some organs (blood, lungs, stomach, pancreas, heart, kidneys, ovaries, brain cortex, hippocampus, foot skin, and microvessels), there were no significant changes, whereas in others we found either a reduced expression (fat, skin, and adrenals) or an enhanced production of AM (cerebellum and colon). These results contradict our initial hypothesis that the increased AM expression found in HHT patients may be due directly to the mutations, but open intriguing questions about the potential phenotypic manifestations of Eng and Acvrl1 mutants that have not yet been studied and that may offer, in the future, a new focus for research on HHT. Full article

(This article belongs to the Special Issue Cardiac Peptides-Current Physiology, Pathophysiology, Biochemistry, Molecular Biology, and Clinical Application)

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Review

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14 pages, 2461 KiB

Open AccessFeature PaperReview

Molecular Mechanism of Blood Pressure Regulation through the Atrial Natriuretic Peptide

by Takeshi Tokudome and Kentaro Otani

Biology 2022, 11(9), 1351; https://doi.org/10.3390/biology11091351 - 14 Sep 2022

Cited by 3 | Viewed by 2776

Abstract

Natriuretic peptides, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), have cardioprotective effects and regulate blood pressure in mammals. ANP and BNP are hormones secreted from the heart into the bloodstream in response to increased preload and [...] Read more.

Natriuretic peptides, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), have cardioprotective effects and regulate blood pressure in mammals. ANP and BNP are hormones secreted from the heart into the bloodstream in response to increased preload and afterload. Both hormones act through natriuretic peptide receptor 1 (NPR1). In contrast, CNP acts through natriuretic peptide receptor 2 (NPR2) and was found to be produced by the vascular endothelium, chondrocytes, and cardiac fibroblasts. Based on its relatively low plasma concentration compared with ANP and BNP, CNP is thought to function as both an autocrine and a paracrine factor in the vasculature, bone, and heart. The cytoplasmic domains of both NPR1 and NPR2 display a guanylate cyclase activity that catalyzes the formation of cyclic GMP. NPR3 lacks this guanylate cyclase activity and is reportedly coupled to G_i-dependent signaling. Recently, we reported that the continuous infusion of the peptide osteocrin, an endogenous ligand of NPR3 secreted by bone and muscle cells, lowered blood pressure in wild-type mice, suggesting that endogenous natriuretic peptides play major roles in the regulation of blood pressure. Neprilysin is a neutral endopeptidase that degrades several vasoactive peptides, including natriuretic peptides. The increased worldwide clinical use of the angiotensin receptor-neprilysin inhibitor for the treatment of chronic heart failure has brought renewed attention to the physiological effects of natriuretic peptides. In this review, we provide an overview of the discovery of ANP and its translational research. We also highlight our recent findings on the blood pressure regulatory effects of ANP, focusing on its molecular mechanisms. Full article

(This article belongs to the Special Issue Cardiac Peptides-Current Physiology, Pathophysiology, Biochemistry, Molecular Biology, and Clinical Application)

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13 pages, 885 KiB

Open AccessReview

NRSF/REST-Mediated Epigenomic Regulation in the Heart: Transcriptional Control of Natriuretic Peptides and Beyond

by Hideaki Inazumi and Koichiro Kuwahara

Biology 2022, 11(8), 1197; https://doi.org/10.3390/biology11081197 - 10 Aug 2022

Viewed by 2423

Abstract

Reactivation of fetal cardiac genes, including those encoding atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), is a key feature of pathological cardiac remodeling and heart failure. Intensive studies on the regulation of ANP and BNP have revealed the involvement of numerous [...] Read more.

Reactivation of fetal cardiac genes, including those encoding atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), is a key feature of pathological cardiac remodeling and heart failure. Intensive studies on the regulation of ANP and BNP have revealed the involvement of numerous transcriptional factors in the regulation of the fetal cardiac gene program. Among these, we identified that a transcriptional repressor, neuron-restrictive silencer factor (NRSF), also named repressor element-1-silencing transcription factor (REST), which was initially detected as a transcriptional repressor of neuron-specific genes in non-neuronal cells, plays a pivotal role in the transcriptional regulation of ANP, BNP and other fetal cardiac genes. Here we review the transcriptional regulation of ANP and BNP gene expression and the role of the NRSF repressor complex in the regulation of cardiac gene expression and the maintenance of cardiac homeostasis. Full article

(This article belongs to the Special Issue Cardiac Peptides-Current Physiology, Pathophysiology, Biochemistry, Molecular Biology, and Clinical Application)

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9 pages, 1073 KiB

Open AccessReview

Effect of Ghrelin on the Cardiovascular System

by Hiroshi Hosoda

Biology 2022, 11(8), 1190; https://doi.org/10.3390/biology11081190 - 08 Aug 2022

Cited by 4 | Viewed by 2331

Abstract

Ghrelin, an n-octanoyl-modified 28-amino-acid-peptide, was first discovered in the human and rat stomach as an endogenous ligand for the growth hormone secretagogue receptor (GHS-R). Ghrelin-GHS-R1a signaling regulates feeding behavior and energy balance, promotes vascular activity and angiogenesis, improves arrhythmia and heart failure, and [...] Read more.

Ghrelin, an n-octanoyl-modified 28-amino-acid-peptide, was first discovered in the human and rat stomach as an endogenous ligand for the growth hormone secretagogue receptor (GHS-R). Ghrelin-GHS-R1a signaling regulates feeding behavior and energy balance, promotes vascular activity and angiogenesis, improves arrhythmia and heart failure, and also protects against cardiovascular disease by suppressing cardiac remodeling after myocardial infarction. Ghrelin’s cardiovascular protective effects are mediated by the suppression of sympathetic activity; activation of parasympathetic activity; alleviation of vascular endothelial dysfunction; and regulation of inflammation, apoptosis, and autophagy. The physiological functions of ghrelin should be clarified to determine its pharmacological potential as a cardiovascular medication. Full article

(This article belongs to the Special Issue Cardiac Peptides-Current Physiology, Pathophysiology, Biochemistry, Molecular Biology, and Clinical Application)

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18 pages, 2511 KiB

Open AccessReview

B-Type Natriuretic Peptide (BNP) Revisited—Is BNP Still a Biomarker for Heart Failure in the Angiotensin Receptor/Neprilysin Inhibitor Era?

by Toshio Nishikimi and Yasuaki Nakagawa

Biology 2022, 11(7), 1034; https://doi.org/10.3390/biology11071034 - 09 Jul 2022

Cited by 9 | Viewed by 3547

Abstract

Myocardial wall stress, cytokines, hormones, and ischemia all stimulate B-type (or brain) natriuretic peptide (BNP) gene expression. Within the myocardium, ProBNP-108, a BNP precursor, undergoes glycosylation, after which a portion is cleaved by furin into mature BNP-32 and N-terminal proBNP-76, depending on the [...] Read more.

Myocardial wall stress, cytokines, hormones, and ischemia all stimulate B-type (or brain) natriuretic peptide (BNP) gene expression. Within the myocardium, ProBNP-108, a BNP precursor, undergoes glycosylation, after which a portion is cleaved by furin into mature BNP-32 and N-terminal proBNP-76, depending on the glycosylation status. As a result, active BNP, less active proBNP, and inactive N-terminal proBNP all circulate in the blood. There are three major pathways for BNP clearance: (1) cellular internalization via natriuretic peptide receptor (NPR)-A and NPR-C; (2) degradation by proteases in the blood, including neprilysin, dipeptidyl-peptidase-IV, insulin degrading enzyme, etc.; and (3) excretion in the urine. Because neprilysin has lower substrate specificity for BNP than atrial natriuretic peptide (ANP), the increase in plasma BNP after angiotensin receptor neprilysin inhibitor (ARNI) administration is much smaller than the increase in plasma ANP. Currently available BNP immunoassays react with both mature BNP and proBNP. Therefore, BNP measured with an immunoassay is mature BNP + proBNP. ARNI administration increases mature BNP but not proBNP, as the latter is not degraded by neprilysin. Consequently, measured plasma BNP initially increases with ARNI administration by the amount of the increase in mature BNP. Later, ARNI reduces myocardial wall stress, and the resultant reduction in BNP production more than offsets the increase in mature BNP mediated by inhibiting degradation by neprilysin, which lowers plasma BNP levels. These results suggest that even in the ARNI era, BNP can be used for diagnosis and assessment of the pathophysiology and prognosis of heart failure, though the mild increases early during ARNI administration should be taken into consideration. Full article

(This article belongs to the Special Issue Cardiac Peptides-Current Physiology, Pathophysiology, Biochemistry, Molecular Biology, and Clinical Application)

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12 pages, 1025 KiB

Open AccessEditor’s ChoiceReview

Roles of Natriuretic Peptides and the Significance of Neprilysin in Cardiovascular Diseases

by Hitoshi Nakagawa and Yoshihiko Saito

Biology 2022, 11(7), 1017; https://doi.org/10.3390/biology11071017 - 06 Jul 2022

Cited by 6 | Viewed by 3550

Abstract

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) activate the guanylyl cyclase A receptor (GC-A), which synthesizes the second messenger cGMP in a wide variety of tissues and cells. C-type natriuretic peptide (CNP) activates the cGMP-producing guanylyl cyclase B receptor (GC-B) in [...] Read more.

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) activate the guanylyl cyclase A receptor (GC-A), which synthesizes the second messenger cGMP in a wide variety of tissues and cells. C-type natriuretic peptide (CNP) activates the cGMP-producing guanylyl cyclase B receptor (GC-B) in chondrocytes, endothelial cells, and possibly smooth muscle cells, cardiomyocytes, and cardiac fibroblasts. The development of genetically modified mice has helped elucidate the physiological roles of natriuretic peptides via GC-A or GC-B. These include the hormonal effects of ANP/BNP in the vasculature, autocrine effects of ANP/BNP in cardiomyocytes, and paracrine effects of CNP in the vasculature and cardiomyocytes. Neprilysin (NEP) is a transmembrane neutral endopeptidase that degrades the three natriuretic peptides. Recently, mice overexpressing NEP, specifically in cardiomyocytes, revealed that local cardiac NEP plays a vital role in regulating natriuretic peptides in the heart tissue. Since NEP inhibition is a clinically accepted approach for heart failure treatment, the physiological roles of natriuretic peptides have regained attention. This article focuses on the physiological roles of natriuretic peptides elucidated in mice with GC-A or GC-B deletion, the significance of NEP in natriuretic peptide metabolism, and the long-term effects of angiotensin receptor-neprilysin inhibitor (ARNI) on cardiovascular diseases. Full article

(This article belongs to the Special Issue Cardiac Peptides-Current Physiology, Pathophysiology, Biochemistry, Molecular Biology, and Clinical Application)

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15 pages, 1164 KiB

Open AccessReview

CNP, the Third Natriuretic Peptide: Its Biology and Significance to the Cardiovascular System

by Yasuaki Nakagawa and Toshio Nishikimi

Biology 2022, 11(7), 986; https://doi.org/10.3390/biology11070986 - 29 Jun 2022

Cited by 10 | Viewed by 3016

Abstract

The natriuretic peptide family consists of three biologically active peptides: ANP, BNP, and CNP. CNP is more widely expressed than the other two peptides, with significant levels in the central nervous system, osteochondral system, and vascular system. The receptor that is mainly targeted [...] Read more.

The natriuretic peptide family consists of three biologically active peptides: ANP, BNP, and CNP. CNP is more widely expressed than the other two peptides, with significant levels in the central nervous system, osteochondral system, and vascular system. The receptor that is mainly targeted by CNP is GC-B, which differs from GC-A, the receptor targeted by ANP and BNP. Consequently, the actions of CNP differ somewhat from those of ANP and BNP. CNP knockout leads to severe dwarfism, and there has been important research into the role of CNP in the osteochondral system. As a result, a CNP analog is now available for clinical use in patients with achondroplasia. In the cardiovascular system, CNP and its downstream signaling are involved in the regulatory mechanisms underlying myocardial remodeling, cardiac function, vascular tone, angiogenesis, and fibrosis, among others. This review focuses on the roles of CNP in the cardiovascular system and considers its potential for clinical application in the treatment of cardiovascular diseases. Full article

(This article belongs to the Special Issue Cardiac Peptides-Current Physiology, Pathophysiology, Biochemistry, Molecular Biology, and Clinical Application)

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11 pages, 1845 KiB

Open AccessReview

Biochemistry of the Endocrine Heart

by Jens P. Goetze, Emil D. Bartels, Theodor W. Shalmi, Lilian Andraud-Dang and Jens F. Rehfeld

Biology 2022, 11(7), 971; https://doi.org/10.3390/biology11070971 - 27 Jun 2022

Viewed by 1870

Abstract

Production and release of natriuretic peptides and other vasoactive peptides are tightly regulated in mammalian physiology and involved in cardiovascular homeostasis. As endocrine cells, the cardiac myocytes seem to possess almost all known chemical necessities for translation, post-translational modifications, and complex peptide proteolysis. [...] Read more.

Production and release of natriuretic peptides and other vasoactive peptides are tightly regulated in mammalian physiology and involved in cardiovascular homeostasis. As endocrine cells, the cardiac myocytes seem to possess almost all known chemical necessities for translation, post-translational modifications, and complex peptide proteolysis. In several ways, intracellular granules in the cells contain not only peptides destined for secretion but also important granin molecules involved in maintaining a regulated secretory pathway. In this review, we will highlight the biochemical phenotype of the endocrine heart recapitulating that the cardiac myocytes are capable endocrine cells. Understanding the basal biochemistry of the endocrine heart in producing and secreting peptides to circulation could lead to new discoveries concerning known peptide products as well as hitherto unidentified cardiac peptide products. In perspective, studies on natriuretic peptides in the heart have shown that the post-translational phase of gene expression is not only relevant for human physiology but may prove implicated also in the development and, perhaps one day, cure of human cardiovascular disease. Full article

(This article belongs to the Special Issue Cardiac Peptides-Current Physiology, Pathophysiology, Biochemistry, Molecular Biology, and Clinical Application)

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15 pages, 1144 KiB

Open AccessReview

Physiological and Pathophysiological Effects of C-Type Natriuretic Peptide on the Heart

by Akihiro Yasoda

Biology 2022, 11(6), 911; https://doi.org/10.3390/biology11060911 - 14 Jun 2022

Cited by 5 | Viewed by 3119

Abstract

C-type natriuretic peptide (CNP) is the third member of the natriuretic peptide family. Unlike other members, i.e., atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), which are cardiac hormones secreted from the atrium and ventricle of the heart, respectively, CNP is regarded [...] Read more.

C-type natriuretic peptide (CNP) is the third member of the natriuretic peptide family. Unlike other members, i.e., atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), which are cardiac hormones secreted from the atrium and ventricle of the heart, respectively, CNP is regarded as an autocrine/paracrine regulator with broad expression in the body. Because of its low expression levels compared to ANP and BNP, early studies failed to show its existence and role in the heart. However, recent studies have revealed the physiological and pathophysiological importance of CNP in the heart; in concert with the distribution of its specific natriuretic peptide receptor-B (NPR-B), CNP has come to be regarded as the major heart-protective natriuretic peptide in the failed heart. NPR-B generates intracellular cyclic guanosine 3′,5′-monophosphate (cGMP) upon CNP binding, followed by various molecular effects including the activation of cGMP-dependent protein kinases, which generates diverse cytoprotective actions in cardiomyocytes, as well as in cardiac fibroblasts. CNP exerts negative inotropic and positive lusitropic responses in both normal and failing heart models. Furthermore, osteocrin, the intrinsic and specific ligand for the clearance receptor for natriuretic peptides, can augment the effects of CNP and may supply a novel therapeutic strategy for cardiac protection. Full article

(This article belongs to the Special Issue Cardiac Peptides-Current Physiology, Pathophysiology, Biochemistry, Molecular Biology, and Clinical Application)

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15 pages, 2154 KiB

Open AccessReview

Natriuretic Peptide-Based Novel Therapeutics: Long Journeys of Drug Developments Optimized for Disease States

by Tomoko Ichiki, Atsushi Jinno and Yoshihisa Tsuji

Biology 2022, 11(6), 859; https://doi.org/10.3390/biology11060859 - 03 Jun 2022

Cited by 7 | Viewed by 2878

Abstract

The field of natriuretic peptides (NPs) as an endocrine hormone has been developing since 1979. There are three peptides in humans: atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), which bind to the guanylyl cyclase-A (GC-A) receptor (also called natriuretic peptide receptor-A [...] Read more.

The field of natriuretic peptides (NPs) as an endocrine hormone has been developing since 1979. There are three peptides in humans: atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), which bind to the guanylyl cyclase-A (GC-A) receptor (also called natriuretic peptide receptor-A (NPR-A)), and C-type natriuretic peptide (CNP), which binds to the GC-B receptor (also called the NPR-B) and then synthesizes intracellular cGMP. GC-A receptor stimulation has natriuretic, vasodilatory, cardiorenal protective and anti-renin–angiotensin–aldosterone system actions, and GC-B receptor stimulation can suppress myocardial fibrosis and can activate bone growth before epiphyseal plate closure. These physiological effects are useful as therapeutics for some disease states, such as heart failure, hypertension, and dwarfism. To optimize the therapeutics for each disease state, we must consider drug metabolism, delivery systems, and target receptor(s). We review the cardiac NP system; new designer NPs, such as modified/combined NPs and modified peptides that can bind to not only NP receptors but receptors for other systems; and oral drugs that enhance endogenous NP activity. Finally, we discuss prospective drug discoveries and the development of novel NP therapeutics. Full article

(This article belongs to the Special Issue Cardiac Peptides-Current Physiology, Pathophysiology, Biochemistry, Molecular Biology, and Clinical Application)

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12 pages, 3403 KiB

Open AccessReview

Receptor Activity Modifying Protein RAMP Sub-Isoforms and Their Functional Differentiation, Which Regulates Functional Diversity of Adrenomedullin

by Takayuki Shindo, Megumu Tanaka, Akiko Kamiyoshi, Yuka Ichikawa-Shindo, Hisaka Kawate and Takayuki Sakurai

Biology 2022, 11(5), 788; https://doi.org/10.3390/biology11050788 - 21 May 2022

Cited by 3 | Viewed by 2386

Abstract

AM knockout (AM-/-) and RAMP2 knockout (RAMP2-/-) proved lethal for mice due to impaired embryonic vascular development. Although most vascular endothelial cell-specific RAMP2 knockout (E-RAMP2-/-) mice also died during the perinatal period, a few E-RAMP2-/- mice reached adulthood. Adult E-RAMP2-/- mice developed spontaneous [...] Read more.

AM knockout (AM-/-) and RAMP2 knockout (RAMP2-/-) proved lethal for mice due to impaired embryonic vascular development. Although most vascular endothelial cell-specific RAMP2 knockout (E-RAMP2-/-) mice also died during the perinatal period, a few E-RAMP2-/- mice reached adulthood. Adult E-RAMP2-/- mice developed spontaneous organ damage associated with vascular injury. In contrast, adult RAMP3 knockout (RAMP3-/-) mice showed exacerbated postoperative lymphedema with abnormal lymphatic drainage. Thus, RAMP2 is essential for vascular development and homeostasis and RAMP3 is essential for lymphatic vessel function. Cardiac myocyte-specific RAMP2 knockout mice showed early onset of heart failure as well as abnormal mitochondrial morphology and function, whereas RAMP3-/- mice exhibited abnormal cardiac lymphatics and a delayed onset of heart failure. Thus, RAMP2 is essential for maintaining cardiac mitochondrial function, while RAMP3 is essential for cardiac lymphangiogenesis. Transplantation of cancer cells into drug-inducible vascular endothelial cell-specific RAMP2 knockout mice resulted in enhanced metastasis to distant organs, whereas metastasis was suppressed in RAMP3-/- mice. RAMP2 suppresses cancer metastasis by maintaining vascular homeostasis and inhibiting vascular inflammation and pre-metastatic niche formation, while RAMP3 promotes cancer metastasis via malignant transformation of cancer-associated fibroblasts. Focusing on the diverse physiological functions of AM and the functional differentiation of RAMP2 and RAMP3 may lead to the development of novel therapeutic strategies. Full article

(This article belongs to the Special Issue Cardiac Peptides-Current Physiology, Pathophysiology, Biochemistry, Molecular Biology, and Clinical Application)

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28 pages, 1531 KiB

Open AccessReview

Endothelin and the Cardiovascular System: The Long Journey and Where We Are Going

by Andreas Haryono, Risa Ramadhiani, Gusty Rizky Teguh Ryanto and Noriaki Emoto

Biology 2022, 11(5), 759; https://doi.org/10.3390/biology11050759 - 16 May 2022

Cited by 16 | Viewed by 3531

Abstract

Endothelin was first discovered more than 30 years ago as a potent vasoconstrictor. In subsequent years, three isoforms, two canonical receptors, and two converting enzymes were identified, and their basic functions were elucidated by numerous preclinical and clinical studies. Over the years, the [...] Read more.

Endothelin was first discovered more than 30 years ago as a potent vasoconstrictor. In subsequent years, three isoforms, two canonical receptors, and two converting enzymes were identified, and their basic functions were elucidated by numerous preclinical and clinical studies. Over the years, the endothelin system has been found to be critical in the pathogenesis of several cardiovascular diseases, including hypertension, pulmonary arterial hypertension, heart failure, and coronary artery disease. In this review, we summarize the current knowledge on endothelin and its role in cardiovascular diseases. Furthermore, we discuss how endothelin-targeting therapies, such as endothelin receptor antagonists, have been employed to treat cardiovascular diseases with varying degrees of success. Lastly, we provide a glimpse of what could be in store for endothelin-targeting treatment options for cardiovascular diseases in the future. Full article

(This article belongs to the Special Issue Cardiac Peptides-Current Physiology, Pathophysiology, Biochemistry, Molecular Biology, and Clinical Application)

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15 pages, 1082 KiB

Open AccessReview

Corin: A Key Mediator in Sodium Homeostasis, Vascular Remodeling, and Heart Failure

by Xianrui Zhang, Xiabing Gu, Yikai Zhang, Ningzheng Dong and Qingyu Wu

Biology 2022, 11(5), 717; https://doi.org/10.3390/biology11050717 - 07 May 2022

Cited by 12 | Viewed by 2705

Abstract

Atrial natriuretic peptide (ANP) is a crucial element of the cardiac endocrine function that promotes natriuresis, diuresis, and vasodilation, thereby protecting normal blood pressure and cardiac function. Corin is a type II transmembrane serine protease that is highly expressed in the heart, where [...] Read more.

Atrial natriuretic peptide (ANP) is a crucial element of the cardiac endocrine function that promotes natriuresis, diuresis, and vasodilation, thereby protecting normal blood pressure and cardiac function. Corin is a type II transmembrane serine protease that is highly expressed in the heart, where it converts the ANP precursor to mature ANP. Corin deficiency prevents ANP activation and causes hypertension and heart disease. In addition to the heart, corin is expressed in other tissues, including those of the kidney, skin, and uterus, where corin-mediated ANP production and signaling act locally to promote sodium excretion and vascular remodeling. These results indicate that corin and ANP function in many tissues via endocrine and autocrine mechanisms. In heart failure patients, impaired natriuretic peptide processing is a common pathological mechanism that contributes to sodium and body fluid retention. In this review, we discuss most recent findings regarding the role of corin in non-cardiac tissues, including the kidney and skin, in regulating sodium homeostasis and body fluid excretion. Moreover, we describe the molecular mechanisms underlying corin and ANP function in supporting orderly cellular events in uterine spiral artery remodeling. Finally, we assess the potential of corin-based approaches to enhance natriuretic peptide production and activity as a treatment of heart failure. Full article

(This article belongs to the Special Issue Cardiac Peptides-Current Physiology, Pathophysiology, Biochemistry, Molecular Biology, and Clinical Application)

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