Compartmentation of Natriuretic Peptide Signalling in Cardiac Myocytes: Effects on Cardiac Contractility and Hypertrophy

Moltzau, Lise Román; Meier, Silja; Andressen, Kjetil Wessel; Levy, Finn Olav

doi:10.1007/978-3-319-54579-0_12

Cited by 2 publications

(2 citation statements)

References 129 publications

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“…Since several PDEs are responsible for tightly regulating cGMP levels in cardiomyocytes, 3 , 5 we wanted to determine which cGMP PDEs displayed activity close to PLB and TnI using our biosensors. First, we assessed the regulation of basal cGMP levels.…”

Section: Resultsmentioning

confidence: 99%

CNP regulates cardiac contractility and increases cGMP near both SERCA and TnI: difference from BNP visualized by targeted cGMP biosensors

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Calamera

Froese

et al. 2021

Cardiovascular Research

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Aims Guanylyl cyclase-B (GC-B; natriuretic peptide receptor-B, NPR-B) stimulation by C-type natriuretic peptide (CNP) increases cGMP and causes a lusitropic and negative inotropic response in adult myocardium. These effects are not mimicked by NPR-A (GC-A) stimulation by brain natriuretic peptide (BNP), despite similar cGMP increase. More refined methods are needed to better understand the mechanisms of the differential cGMP signaling and compartmentation. The aim of this work was to measure cGMP near proteins involved in regulating contractility to understand compartmentation of cGMP signaling in adult cardiomyocytes. Methods and Results We constructed several fluorescence resonance energy transfer (FRET)-based biosensors for cGMP subcellularly targeted to phospholamban (PLB) and troponin I (TnI). CNP stimulation of adult rat cardiomyocytes increased cGMP near PLB and TnI, whereas BNP stimulation increased cGMP near PLB, but not TnI. The phosphodiesterases PDE2 and PDE3 constrained cGMP in both compartments. Local receptor stimulation aided by scanning ion conductance microscopy (SICM) combined with FRET revealed that CNP stimulation both in the t-tubules and on the cell crests increases cGMP similarly near both TnI and PLB. In ventricular strips, CNP stimulation, but not BNP, induced a lusitropic response, enhanced by inhibition of either PDE2 or PDE3, and a negative inotropic response. In cardiomyocytes from heart failure rats, CNP increased cGMP near PLB and TnI more pronounced than in cells from sham-operated animals. Conclusions These targeted biosensors demonstrate that CNP, but not BNP, increases cGMP near TnI in addition to PLB, explaining how CNP, but not BNP is able to induce lusitropic and negative inotropic responses. Translational Perspective Although best known as heart failure biomarkers, natriuretic peptides (ANP, BNP and CNP) are important signaling molecules in the heart and other organs through increasing cyclic GMP (cGMP). Treatment preventing their degradation improves heart failure prognosis. To better understand their cardiac signaling, we employed fluorescent cGMP biosensors targeted to troponin I and phospholamban and found that BNP and CNP increase cGMP differently around these proteins in both normal and failing cardiomyocytes. This may explain the different effects of BNP and CNP on cardiac contractility and relaxation, with possible implications for understanding and treatment of heart failure.

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Section: Resultsmentioning

confidence: 99%

CNP regulates cardiac contractility and increases cGMP near both SERCA and TnI: difference from BNP visualized by targeted cGMP biosensors

Manfra

Calamera

Froese

et al. 2021

Cardiovascular Research

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“…In Longshanks growth plates, the apparently reduced presence of NPR3 protein in the proliferative zone ( Supplementary Figure S2C ) may increase the bioavailability of CNP, thus stimulating/maintaining chondrocyte proliferation. Npr3 may also be linked to the activation of the NKA pump but the exact activation mechanism is not entirely resolved ( Moltzau et al, 2017 ). Interestingly, our previous work indicates that Fxyd2 expression is downregulated in hypertrophic chondrocytes of tibiae cultured with CNP, suggesting a link between Npr3 and Fxyd2 expression ( Agoston et al, 2007 ), and therefore a potential link in the downregulation of these two transcripts in both Longshanks lines.…”

Section: Discussionmentioning

confidence: 99%

A Na+/K+ ATPase Pump Regulates Chondrocyte Differentiation and Bone Length Variation in Mice

Marchini

Ashkin

Bellini

et al. 2021

Front. Cell Dev. Biol.

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The genetic and developmental mechanisms involved in limb formation are relatively well documented, but how these mechanisms are modulated by changes in chondrocyte physiology to produce differences in limb bone length remains unclear. Here, we used high throughput RNA sequencing (RNAseq) to probe the developmental genetic basis of variation in limb bone length in Longshanks, a mouse model of experimental evolution. We find that increased tibia length in Longshanks is associated with altered expression of a few key endochondral ossification genes such as Npr3, Dlk1, Sox9, and Sfrp1, as well reduced expression of Fxyd2, a facultative subunit of the cell membrane-bound Na+/K+ ATPase pump (NKA). Next, using murine tibia and cell cultures, we show a dynamic role for NKA in chondrocyte differentiation and in bone length regulation. Specifically, we show that pharmacological inhibition of NKA disrupts chondrocyte differentiation, by upregulating expression of mesenchymal stem cell markers (Prrx1, Serpina3n), downregulation of chondrogenesis marker Sox9, and altered expression of extracellular matrix genes (e.g., collagens) associated with proliferative and hypertrophic chondrocytes. Together, Longshanks and in vitro data suggest a broader developmental and evolutionary role of NKA in regulating limb length diversity.

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Compartmentation of Natriuretic Peptide Signalling in Cardiac Myocytes: Effects on Cardiac Contractility and Hypertrophy

Cited by 2 publications

References 129 publications

CNP regulates cardiac contractility and increases cGMP near both SERCA and TnI: difference from BNP visualized by targeted cGMP biosensors

CNP regulates cardiac contractility and increases cGMP near both SERCA and TnI: difference from BNP visualized by targeted cGMP biosensors

A Na+/K+ ATPase Pump Regulates Chondrocyte Differentiation and Bone Length Variation in Mice

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