A State of Natriuretic Peptide Deficiency

Nyberg, Michael; Terzic, Dijana; Ludvigsen, Trine Pagh; Mark, Peter; Michaelsen, Natasha B; Abildstrøm, Steen Zabell; Engelmann, Mads D.M.; Richards, A. Mark; Goetze, Jens P.

doi:10.1210/endrev/bnac029

Cited by 10 publications

(3 citation statements)

References 142 publications

(124 reference statements)

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“…Additional to a role of CNP, the effects of NPR3 could also be mediated via changes in endogenous levels of ANP and BNP, as perturbations in this part of the natriuretic peptide systems are also important in the aetiology of CVD [ 4 , 45 , 46 ]. An increase in the levels of the three peptides because of reduced NPR3-mediated clearance could potentially reduce CVD risk in a blood pressure-independent manner via anti-hypertrophic, anti-apoptotic, anti-fibrotic and/or anti-inflammatory effects directly related to natriuretic peptide signalling in the cardiovascular system [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

“…C-type natriuretic peptide (CNP) belongs to the family of natriuretic peptides including atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), which are collectively involved in regulating the structure and function of the cardiovascular system [ 4 – 6 ]. In accordance with this role of CNP in the cardiovascular system, preclinical observations have provided evidence for perturbations in CNP signalling being involved in the development of CVD [ 7 – 9 ].…”

Section: Introductionmentioning

confidence: 99%

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Genetic evidence implicating natriuretic peptide receptor-3 in cardiovascular disease risk: a Mendelian randomization study

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Karhunen

Hovingh

et al. 2023

BMC Med

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Background C-type natriuretic peptide (CNP) is a known target for promoting growth and has been implicated as a therapeutic opportunity for the prevention and treatment of cardiovascular disease (CVD). This study aimed to explore the effect of CNP on CVD risk using the Mendelian randomization (MR) framework. Methods Instrumental variables mimicking the effects of pharmacological intervention on CNP were identified as uncorrelated genetic variants located in the genes coding for its primary receptors, natriuretic peptide receptors-2 and 3 (NPR2 and NPR3), that associated with height. We performed MR and colocalization analyses to investigate the effects of NPR2 signalling and NPR3 function on CVD outcomes and risk factors. MR estimates were compared to those obtained when considering height variants from throughout the genome. Results Genetically-proxied reduced NPR3 function was associated with a lower risk of CVD, with odds ratio (OR) 0.74 per standard deviation (SD) higher NPR3-predicted height, and 95% confidence interval (95% CI) 0.64–0.86. This effect was greater in magnitude than observed when considering height variants from throughout the genome. For CVD subtypes, similar MR associations for NPR3-predicted height were observed when considering the outcomes of coronary artery disease (0.75, 95% CI 0.60–0.92), stroke (0.69, 95% CI 0.50–0.95) and heart failure (0.77, 95% CI 0.58–1.02). Consideration of CVD risk factors identified systolic blood pressure (SBP) as a potential mediator of the NPR3-related CVD risk lowering. For stroke, we found that the MR estimate for NPR3 was greater in magnitude than could be explained by a genetically predicted SBP effect alone. Colocalization results largely supported the MR findings, with no evidence of results being driven by effects due to variants in linkage disequilibrium. There was no MR evidence supporting effects of NPR2 on CVD risk, although this null finding could be attributable to fewer genetic variants being identified to instrument this target. Conclusions This genetic analysis supports the cardioprotective effects of pharmacologically inhibiting NPR3 receptor function, which is only partly mediated by an effect on blood pressure. There was unlikely sufficient statistical power to investigate the cardioprotective effects of NPR2 signalling.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genetic evidence implicating natriuretic peptide receptor-3 in cardiovascular disease risk: a Mendelian randomization study

Cronjé

Karhunen

Hovingh

et al. 2023

BMC Med

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“…C‐type natriuretic peptide (CNP) is released by endothelial cells, fibroblasts and cardiomyocytes in the heart where it elicits autocrine and paracrine signalling via its interaction with natriuretic peptide receptor (NPR) 2 and NPR3 (Cerra & Pellegrino, 2007 ; Moyes & Hobbs, 2019 ; Nyberg et al., 2023 ). NPR2 is a particulate guanylyl cyclase that catalyses the synthesis of cyclic guanosine monophosphate (cGMP) whereas NPR3 clears CNP via a receptor‐mediated internalization and degradation process, but a signalling function (G i protein‐linked receptor) has also been reported (Moyes & Hobbs, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

C‐type natriuretic peptide induces inotropic and lusitropic effects in human 3D‐engineered cardiac tissue: Implications for the regulation of cardiac function in humans

Bachmann

Kirchhoff

Napolitano³

et al. 2023

Experimental Physiology

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The role of C‐type natriuretic peptide (CNP) in the regulation of cardiac function in humans remains to be established as previous investigations have been confined to animal model systems. Here, we used well‐characterized engineered cardiac tissues (ECTs) generated from human stem cell‐derived cardiomyocytes and fibroblasts to study the acute effects of CNP on contractility. Application of CNP elicited a positive inotropic response as evidenced by increases in maximum twitch amplitude, maximum contraction slope and maximum calcium amplitude. This inotropic response was accompanied by a positive lusitropic response as demonstrated by reductions in time from peak contraction to 90% of relaxation and time from peak calcium transient to 90% of decay that paralleled increases in maximum contraction decay slope and maximum calcium decay slope. To establish translatability, CNP‐induced changes in contractility were also assessed in rat ex vivo (isolated heart) and in vivo models. Here, the effects on force kinetics observed in ECTs mirrored those observed in both the ex vivo and in vivo model systems, whereas the increase in maximal force generation with CNP application was only detected in ECTs. In conclusion, CNP induces a positive inotropic and lusitropic response in ECTs, thus supporting an important role for CNP in the regulation of human cardiac function. The high degree of translatability between ECTs, ex vivo and in vivo models further supports a regulatory role for CNP and expands the current understanding of the translational value of human ECTs.New Findings What is the central question of this study? What are the acute responses to C‐type natriuretic peptide (CNP) in human‐engineered cardiac tissues (ECTs) on cardiac function and how well do they translate to matched concentrations in animal ex vivo and in vivo models? What is the main finding and its importance? Acute stimulation of ECTs with CNP induced positive lusitropic and inotropic effects on cardiac contractility, which closely reflected the changes observed in rat ex vivo and in vivo cardiac models. These findings support an important role for CNP in the regulation of human cardiac function and highlight the translational value of ECTs.

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