Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathogenesis of hypertension, as a multifactorial trait, is complex. High blood pressure levels, in turn, concur with the development of cardiovascular damage. Abnormalities of several neurohormonal mechanisms controlling blood pressure homeostasis and cardiovascular remodeling can contribute to these pathological conditions. The natriuretic peptide (NP) family (including ANP (atrial natriuretic peptide), BNP (brain natriuretic peptide), and CNP (C-type natriuretic peptide)), the NP receptors (NPRA, NPRB, and NPRC), and the related protease convertases (furin, corin, and PCSK6) constitute the NP system and represent relevant protective mechanisms toward the development of hypertension and associated conditions, such as atherosclerosis, stroke, myocardial infarction, heart failure, and renal injury. Initially, several experimental studies performed in different animal models demonstrated a key role of the NP system in the development of hypertension. Importantly, these studies provided relevant insights for a better comprehension of the pathogenesis of hypertension and related cardiovascular phenotypes in humans. Thus, investigation of the role of NPs in hypertension offers an excellent example in translational medicine. In this review article, we will summarize the most compelling evidence regarding the molecular mechanisms underlying the physiological and pathological impact of NPs on blood pressure regulation and on hypertension development. We will also discuss the protective effect of NPs toward the increased susceptibility to hypertensive target organ damage.
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PMID:Molecular Implications of Natriuretic Peptides in the Protection from Hypertension and Target Organ Damage Development. 3078 51

Aortic valve stenosis (AS) is the most common heart valve disease in North America and Europe leading to an increased risk of heart failure and death. A multidisciplinary evaluation of symptoms, individual risk profile, echocardiographic parameters, biomarkers assessment is required for an appropriate clinical and therapeutic management of AS. The natriuretic peptides (NPs) represent an important biomarker for diagnostic, prognostic and therapeutic purposes in several cardiovascular diseases. The present review article provides an overview of the current knowledge on the role of NPs in the pathogenesis, diagnosis, risk stratification and potential therapeutic implications in AS. C-type natriuretic peptide (CNP) level is reduced in AS, favoring the formation of calcified aggregates and an increased expression of bone-related transcripts and proteins (Runx2, osteonectin, osteocalcin, alkaline phospahatase). Consistent results were obtained through the inhibition of the type A and B natriuretic peptide receptors (NPRA, NPRB) and of the proprotein convertase furin expression. Increased plasma B-type natriuretic peptide (BNP) level contributes to monitor the progression of AS and to identify patients who would most benefit from an early therapeutic intervention, such as surgical or transcatheter aortic valve replacement. Moreover, a risk stratification of AS patients that takes into account the NPs level has a major impact toward the occurrence of heart failure, syncope and sudden cardiac death. Finally, the development of novel therapeutic strategies, such as the neprilysin inhibition, may represent a suitable pharmacological approach for the treatment of AS. Due to the above mentioned multiple roles, NPs represent key players in AS development, management and treatment.
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PMID:Molecular and clinical implications of natriuretic peptides in aortic valve stenosis. 3087 94

Atrial natriuretic peptide (ANP) is a peptide hormone that in response to atrial stretch is secreted from atrial myocytes into the circulation, where it stimulates vasodilatation and natriuresis. ANP is an important biomarker of heart failure where low plasma concentrations exclude cardiac dysfunction. ANP is a member of the natriuretic peptide (NP) family, which also includes the B-type natriuretic peptide (BNP) and the C-type natriuretic peptide. The proforms of these hormones undergo processing to mature peptides, and for proBNP, this process has previously been demonstrated to be regulated by O-glycosylation. It has been suggested that proANP also may undergo post-translational modifications. Here, we conducted a targeted O-glycoproteomics approach to characterize O-glycans on NPs and demonstrate that all NP members can carry O-glycans. We identified four O-glycosites in proANP in the porcine heart, and surprisingly, two of these were located on the mature bioactive ANP itself. We found that one of these glycans is located within a conserved sequence motif of the receptor-binding region, suggesting that O-glycans may serve a function beyond intracellular processing and maturation. We also identified an O-glycoform of proANP naturally occurring in human circulation. We demonstrated that site-specific O-glycosylation shields bioactive ANP from proteolytic degradation and modifies potency at its cognate receptor in vitro Furthermore, we showed that ANP O-glycosylation attenuates acute renal and cardiovascular ANP actions in vivo The discovery of novel glycosylated ANP proteoforms reported here significantly improves our understanding of cardiac endocrinology and provides important insight into the etiology of heart failure.
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PMID:Discovery of O-glycans on atrial natriuretic peptide (ANP) that affect both its proteolytic degradation and potency at its cognate receptor. 3178 77

The natriuretic peptide (NP) system is composed of 3 distinct peptides (atrial natriuretic peptide or ANP, B-type natriuretic peptide or BNP, and C-type natriuretic peptide or CNP) and 3 receptors (natriuretic peptide receptor-A or NPR-A or particulate guanynyl cyclase-A natriuretic peptide receptor-B or NPR-B or particulate guanynyl cyclase-B, and natriuretic peptide receptor-C or NPR-C or clearance receptor). ANP and BNP function as defense mechanisms against ventricular stress and the deleterious effects of volume and pressure overload on the heart. Although the role of NPs in cardiovascular homeostasis has been extensively studied and well established, much remains uncertain about the signaling pathways in pathological states like heart failure, a state of impaired natriuretic peptide function. Elevated levels of ANP and BNP in heart failure correlate with disease severity and have a prognostic value. Synthetic ANP and BNP have been studied for their therapeutic role in hypertension and heart failure, and promising trials are under way. In recent years, the expression of ANP and BNP in human adipocytes has come to light. Through their role in promotion of adipocyte browning, lipolysis, lipid oxidation, and modulation of adipokine secretion, they have emerged as key regulators of energy consumption and metabolism. NPR-A signaling in skeletal muscles and adipocytes is emerging as pivotal to the maintenance of long-term insulin sensitivity, which is disrupted in obesity and reduced glucose-tolerance states. Genetic variants in the genes encoding for ANP and BNP have been associated with a favorable cardiometabolic profile. In this review, we discuss several pathways that have been proposed to explain the role of NPs as endocrine networkers. There is much to be explored about the therapeutic role of NPs in improving metabolic milieu.
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PMID:The Importance of Natriuretic Peptides in Cardiometabolic Diseases. 3253 42

Heart failure is often accompanied by titin-dependent myocardial stiffness. Phosphorylation of titin by cGMP-dependent protein kinase I (PKGI) increases cardiomyocyte distensibility. The upstream pathways stimulating PKGI-mediated titin phosphorylation are unclear. We studied whether C-type natriuretic peptide (CNP), via its guanylyl cyclase-B (GC-B) receptor and cGMP/PKGI signaling, modulates titin-based ventricular compliance. To dissect GC-B-mediated effects of endogenous CNP in cardiomyocytes, we generated mice with cardiomyocyte-restricted GC-B deletion (CM GC-B-KO mice). The impact on heart morphology and function, myocyte passive tension, and titin isoform expression and phosphorylation was studied at baseline and after increased afterload induced by transverse aortic constriction (TAC). Pressure overload increased left ventricular endothelial CNP expression, with an early peak after 3 days. Concomitantly, titin phosphorylation at Ser4080, the site phosphorylated by PKGI, was augmented. Notably, in CM GC-B-KO mice this titin response was abolished. TAC-induced hypertrophy and fibrosis were not different between genotypes. However, the KO mice presented mild systolic and diastolic dysfunction together with myocyte stiffness, which were not observed in control littermates. In vitro, recombinant PKGI rescued reduced titin-Ser4080 phosphorylation and reverted passive stiffness of GC-B-deficient cardiomyocytes. CNP-induced activation of GC-B/cGMP/PKGI signaling in cardiomyocytes provides a protecting regulatory circuit preventing titin-based myocyte stiffening during early phases of pressure overload.
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PMID:C-type natriuretic peptide moderates titin-based cardiomyocyte stiffness. 3305 20


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