Natriuretic Peptide Receptor-C Protects Against Angiotensin II-Mediated Sinoatrial Node Disease in Mice

Mackasey, Martin; Egom, Emmanuel E.; Jansen, Hailey J.; Hua, Rui; Moghtadaei, Motahareh; Liu, Yingjie; Kaur, Jasbinder; McRae, Megan D.; Bogachev, Oleg; Rafferty, Sara A.; Ray, Gibanananda; Kirkby, Adam W.; Rose, Robert A.

doi:10.1016/j.jacbts.2018.08.004

Cited by 30 publications

(37 citation statements)

References 72 publications

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“…Representative activation maps (Fig. 3A) illustrate that conduction initiates in the right atrial posterior wall and then spreads across the full atrial preparation (21)(22)(23). These representative maps show that total conduction time across the full atrial preparation is longer in Akita mice.…”

Section: Resultsmentioning

confidence: 95%

Loss of insulin signaling may contribute to atrial fibrillation and atrial electrical remodeling in type 1 diabetes

Polina

Jansen

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Atrial fibrillation (AF) is prevalent in diabetes mellitus (DM); however, the basis for this is unknown. This study investigated AF susceptibility and atrial electrophysiology in type 1 diabetic Akita mice using in vivo intracardiac electrophysiology, high-resolution optical mapping in atrial preparations, and patch clamping in isolated atrial myocytes. qPCR and western blotting were used to assess ion channel expression. Akita mice were highly susceptible to AF in association with increased P-wave duration and slowed atrial conduction velocity. In a second model of type 1 DM, mice treated with streptozotocin (STZ) showed a similar increase in susceptibility to AF. Chronic insulin treatment reduced susceptibility and duration of AF and shortened P-wave duration in Akita mice. Atrial action potential (AP) morphology was altered in Akita mice due to a reduction in upstroke velocity and increases in AP duration. In Akita mice, atrial Na+current (INa) and repolarizing K+current (IK) carried by voltage gated K+(Kv1.5) channels were reduced. The reduction in INaoccurred in association with reduced expression ofSCN5aand voltage gated Na+(NaV1.5) channels as well as a shift in INaactivation kinetics. Insulin potently and selectively increased INain Akita mice without affecting IK. Chronic insulin treatment increased INain association with increased expression of NaV1.5. Acute insulin also increased INa, although to a smaller extent, due to enhanced insulin signaling via phosphatidylinositol 3,4,5-triphosphate (PIP3). Our study reveals a critical, selective role for insulin in regulating atrial INa, which impacts susceptibility to AF in type 1 DM.

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Section: Resultsmentioning

confidence: 95%

Loss of insulin signaling may contribute to atrial fibrillation and atrial electrical remodeling in type 1 diabetes

Polina

Jansen

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…This does not mean that NPR-B cannot be targeted pharmacologically, as recent studies suggest that novel designer peptides that bind to NPR-B can reduce fibroblast proliferation and collagen secretion in vitro and in vivo [128,149,150]. This role of endogenous NPR-C signalling in regulating fibrosis is supported by other studies that have observed greater cardiac dysfunction, atrial collagen deposition, and higher levels of TGFβ and TIMP1 in NPR-C KO mice subjected to angiotensin II-induced pressure overload [151,152]. Furthermore, a functional genetic variant in NPR-C has been discovered in humans that is associated with diastolic dysfunction.…”

Section: Endogenous Cnp Is Cardioprotective In Animal Models Of Hementioning

confidence: 84%

C-Type Natriuretic Peptide: A Multifaceted Paracrine Regulator in the Heart and Vasculature

Moyes

Hobbs

2019

IJMS

109

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C-type natriuretic peptide (CNP) is an autocrine and paracrine mediator released by endothelial cells, cardiomyocytes and fibroblasts that regulates vital physiological functions in the cardiovascular system. These roles are conveyed via two cognate receptors, natriuretic peptide receptor B (NPR-B) and natriuretic peptide receptor C (NPR-C), which activate different signalling pathways that mediate complementary yet distinct cellular responses. Traditionally, CNP has been deemed the endothelial component of the natriuretic peptide system, while its sibling peptides, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), are considered the endocrine guardians of cardiac function and blood volume. However, accumulating evidence indicates that CNP not only modulates vascular tone and blood pressure, but also governs a wide range of cardiovascular effects including the control of inflammation, angiogenesis, smooth muscle and endothelial cell proliferation, atherosclerosis, cardiomyocyte contractility, hypertrophy, fibrosis, and cardiac electrophysiology. This review will focus on the novel physiological functions ascribed to CNP, the receptors/signalling mechanisms involved in mediating its cardioprotective effects, and the development of therapeutics targeting CNP signalling pathways in different disease pathologies.

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“…Sangaralingham and colleagues also demonstrated that NPR-C may mediate the antifibrotic and antiproliferative peptide CNP in cultured adult human cardiac fibroblasts [46]. Furthermore, we recently showed that mice lacking NPR-C exhibit enhanced collagen expression and deposition in the atria [47,48], whereas selective NPR-C activation may prevent pathological collagen deposition [49]. The activation of NPR-C signaling may inhibit the hypoxia-induced vascular endothelial cell growth factor (VEGF) transcription and protein production, suggesting that this receptor may have both direct [50], and indirect effects as antiproliferation factors for endothelial cells (EC), the latter potentially mediated via modulating VEGF synthesis [51].…”

Section: Npr-c Signaling As a Therapeutic Target In Tissue Remodelingmentioning

confidence: 99%

Pulmonary Arterial Hypertension Due to NPR-C Mutation: A Novel Paradigm for Normal and Pathologic Remodeling?

Egom

2019

IJMS

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Idiopathic Pulmonary Arterial Hypertension (IPAH) is a deadly and disabling disease characterized by severe vascular remodeling of small pulmonary vessels by fibroblasts, myofibroblasts and vascular smooth muscle cell proliferation. Recent studies suggest that the Natriuretic Peptide Clearance Receptor (NPR-C) signaling pathways may play a crucial role in the development of IPAH. Reduced expression or function of NPR-C signaling in pulmonary artery smooth muscle cells may contribute to the pulmonary vascular remodeling, which is characteristic of this disease. The likely mechanisms may involve an impaired interaction between NPR-C, specific growth factors and other signal transduction pathways including but not limited to Gqα/mitogen-activated protein kinase (MAPK)/PI3K and AKT signaling. The resulting failure of growth suppression in pulmonary artery smooth muscle cells provides critical clues to the cellular pathobiology of IPAH. The reciprocal regulation of NPR-C signaling in models of tissue remodeling may thus provide new insights to our understanding of IPAH.

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Natriuretic Peptide Receptor-C Protects Against Angiotensin II-Mediated Sinoatrial Node Disease in Mice

Abstract: Visual Abstract

Cited by 30 publications

References 72 publications

Loss of insulin signaling may contribute to atrial fibrillation and atrial electrical remodeling in type 1 diabetes

Loss of insulin signaling may contribute to atrial fibrillation and atrial electrical remodeling in type 1 diabetes

C-Type Natriuretic Peptide: A Multifaceted Paracrine Regulator in the Heart and Vasculature

Pulmonary Arterial Hypertension Due to NPR-C Mutation: A Novel Paradigm for Normal and Pathologic Remodeling?

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