The Impact of Natriuretic Peptides on Heart Development, Homeostasis, and Disease
Abstract
:1. Introduction of Natriuretic Peptides
2. Regulation of NPPA and NPPB Expression during Development and Disease
3. Natriuretic Peptide Production and Receptor Interactions
4. The Role of NPs in CM Cell Cycle Activity during Development, Maturation, and Stress
5. The Role of NPs in CM Hypertrophy
6. Role of NPs in Cardiac Contractility
7. Role of NPs in Cardiac Fibrosis and Inflammation
8. NPs in Cardiac Energy Metabolism and Mitochondrial Function
9. Role of NPs in Cardiac Rhythm
10. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Conflicts of Interest
Abbreviation
ANP | Atrial natriuretic peptide |
ANF | Atrial natriuretic factor |
BNP | B-type/Brain natriuretic peptide |
CNP | C-type natriuretic peptide |
NPR-A | Natriuretic peptide receptor-A |
NRP-B | Natriuretic peptide receptor-B |
NRP-C | Natriuretic peptide receptor-C |
Nppa | Natriuretic peptide A |
Nppb | Natriuretic peptide B |
Nppc | Natriuretic peptide C |
Npr1 | Natriuretic peptide receptor-1 |
Npr2 | Natriuretic peptide receptor-2 |
Npr3 | Natriuretic peptide receptor-3 |
References
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Hypertrophy | ||||||
---|---|---|---|---|---|---|
NPs or NP receptors | Experimental model | Manipulation | Age/species | Intracardiac observations | Proposed pathways | Ref. |
Npr1 | Global KO | None | E15.5, ND1 | Increased heart size, reduced number of nuclei | N/A | [12] |
Npr1 | Global KO | None | 4 months, 12 months/mice | Increased CM size, increased fibrosis | N/A | [13] |
Npr1 | Global KO | TRPC channel inhibition+ Ang II treatment | 12 weeks/mice | Reduction in hypertrophy | ANP/cGMP/PKG inhibition of the Ca2+ channel TRPC6 activity | [14] |
Npr1 | Global KO | NPRA−/− x RGS4 CM-specific OE | 16 weeks/mice | Reduction in hypertrophy | NPRA/RGS4-mediated suppression of the calcineurin–NFAT pathway | [15] |
Npr1 | Global KO | NPRA−/− NPRA−/− x AT1−/− DKO | 16 weeks/mice | CM hypertrophy Attenuated hypertrophic response | N/A | [16] |
Npr1 | Global KO | NPRA−/− + MI NPRA−/− x AT1−/− DKO + MI | 8–10 weeks/mice | CM hypertrophy Attenuated hypertrophic response | N/A | [17] |
Npr1 | Global KO | Calcineurin inhibitor (FK506) | 14 weeks/mice | Reduction in hypertrophy, decreased fibrosis | ANP pathway antagonizes the calcineurin–NFAT pathway to regulate the hypertrophic response | [18] |
Npr1 | Global KO | None | Neonatal (P2), young (4 weeks), adult mice (22 weeks) | Increased CM hypertrophy, increased fibrosis | NF-kB/AP1-mediated MPP activation (fibrosis) disruption of sarcoplasmic reticulum Ca2+ handling (hypertrophy) | [19] |
MMP-inhibition | adult mice (22 weeks) | Increased hypertrophy, decreased fibrosis | ||||
Npr1 | Global KO | TAC | 3–6 months/mice | Cardiac hypertrophy | N/A | [20] |
Npr1 | Global KO | None | 8–12 weeks/mice | CM hypertrophy | N/A | [21] |
CM-specific NPRA OE | None | CM cell size reduction | ||||
Global KO x CM-specific CM NPRA OE | None | Reduced hypertrophic response | ||||
Npr1 | Global KO | Consecutive pregnancy–lactation cycles | 8 weeks/mice | Lactation-induced cardiac hypertrophy | NP/NPRA suppressed aldosterone/MR signaling and cardiac IL-6 expression | [22] |
CM-specific KO | ||||||
Npr1 | CM-specific KO | TAC | 8–12 weeks/mice | CM hypertrophy | ANP/cGMP/cGKI-mediated inhibition of MR nuclear translocation | [23] |
TAC+ MR agonist (eplerenone) | Attenuation of CM hypertrophy | |||||
Npr1 | CM-specific KO | Treatment with AngII/ISO | 4–6 weeks/mice | CM hypertrophy | ANP/cGMP/PKG I/RGS2-mediated suppression of Ang II-stimulated Ca2+ handling | [24] |
Npr1 | CM-specific constitutively active NPRA | ISO infusion/AAC | 8–12 weeks/mice | Prevention of CM hypertrophy | N/A | [25] |
Npr1 | Global constitutively active NPRA | None | 12 weeks/mice | Male-specific CM size reduction | NP/NPRA-mediated reduction of ERK1/2 activity | [26] |
Npr1 | Global Npr1++/++ | None | 24–26 weeks/mice | Decreased CM area, reduced inflammatory cytokines, | NPRA/cGMP/mediated suppression of Nf-KB/AP1 | [27] |
Nppa | Global KO | TAC | 10 weeks | Increased hypertrophy, increased ECM gene expression | N/A | [28] |
Nppa | Global KO | Nppa+/− + TAC Nppa−/− + TAC | 9–12 weeks/mice | Dose-dependent cardiac hypertrophy in untreated and TAC mice | N/A | [29] |
Nppa | Global KO | Aorto-caval fistula (ACF) for volume overload and low-salt diet | 8–10 weeks/mice | Increased hypertrophy | N/A | [30] |
Nppa | Global KO | Low-salt diet | 8–9 weeks/mice | Increased CM hypertrophy | N/A | [31] |
Nppa | Global KO | MI MI + ANP infusion | 6–24 weeks/mice | Increased hypertrophy | N/A | [32] |
Nppb | Global KO | none | 4–8 weeks/rats | Progressive hypertrophy, hypertension fibrosis | N/A | [33] |
AAV9-rBNP for 9 months | 9 months/rats | Reduced hypertrophy | ||||
BNP | AAV9-rBNP for 9 months | Normotensive | 3-4 weeks/rats | Prevention of age-associated hypertrophy and fibrosis | N/A | [34] |
Spontaneously hypertensive rat model | Prevention of hypertension-associated hypertrophy and fibrosis | |||||
CNP/Npr3 | CM-specific deletion | none | Adult/mice | Preserved cardiac functionality, no increase in hypertrophy or fibrosis | N/A | [35] |
Abdominal aortic constriction | Functional decline, increased hypertrophic response, fibrosis | |||||
Isoproterenol | ||||||
Angiotensin II | Increased hypertrophic response | |||||
Angiotensin II + CNP | Decreased hypertrophic response | |||||
IR | Increased infarct size, prolonged impairment in LV function | |||||
Npr3 global deletion | none | Preserved cardiac functionality, no increase in hypertrophy or fibrosis | ||||
Abdominal aortic constriction | Functional decline, increased hypertrophic response, fibrosis | |||||
Abdominal aortic constriction + CNP | No reversal of pathologic remodeling | |||||
IR | Increased infarct size, prolonged impairment in LV function | |||||
Fibrosis | ||||||
NPs or NP receptors | Experimental model | Manipulation | Age/species | Intracardiac observations | Proposed pathways | Ref. |
Npr1 | Global KO | Consecutive pregnancy–lactation cycles | 8 weeks/mice | Lactation-induced cardiac hypertrophy+ fibrosis | NP/NPRA suppressed aldosterone/MR signaling and cardiac IL-6 expression | [22] |
CM-specific KO | ||||||
Npr1 | Global KO | None | Neonatal (P2), young (4 weeks), adult mice (22 weeks) | Increased CM hypertrophy, increased fibrosis | NF-kB/AP-1-mediated MPP activation (fibrosis) disruption of sarcoplasmic reticulum Ca2+ handling (hypertrophy) | [19] |
MMP-inhibition | Adult mice (22 weeks) | Increased hypertrophy, decreased fibrosis | ||||
Npr1 | Global KO | 30 min I/R | 10–14 weeks/mice | N/A | NPRA-mediated suppression of NF-kB-mediated inflammatory processes | [36] |
Npr1 | Global Npr1++/++ | None | 24–26 weeks/mice | Decreased CM area, reduced inflammatory cytokines, | NPRA/cGMP-mediated suppression of Nf-KB/AP1 | [27] |
Npr3 | Global KO | Npr3−/− | 20 weeks/mice | No effect on left ventricular and left atrial fibrosis | NPRC deletion results in cAMP/PKA- and cGMP/PKG-mediated TGIF1 upregulation | [37] |
Npr3−/− with STZ-induced diabetic cardiomyopathy | Attenuation of diabetes-induced cardiac fibrosis, no difference in atrial fibrosis | |||||
AAV9-shNPRC | AAV9-shNPRC with STZ-induced diabetic cardiomyopathy | Attenuation of diabetes-induced cardiac fibrosis | ||||
Nppa | Global KO | Nppa+/− + TAC Nppa−/− + TAC | 9–12 weeks/mice | Dose-dependent cardiac hypertrophy and fibrosis both in untreated and TAC mice | N/A | [29] |
Nppa | Global KO | Nppa−/− + I/R | 8–10 weeks/mice | Increased infarct size and reduced autophagy | ANP/NPR1/PRKG-mediated stimulation of autophagy through activation of TFEB | [38] |
BNP | hAAV5-BNP intracardiac injection | Unmanipulated | rats | Reduced fibrosis, increase capillary density | N/A | [39] |
MI | Improved cardiac function | Normalization of SERCA2 expression and PLN phosphorylation | ||||
Ang II infusion | Decreased fibrosis | N/A | ||||
Nppb | Global KO | None | 20 weeks/mice | Increased fibrosis | N/A | [40] |
AAC | ||||||
Nppb | Global KO | None | 20 weeks/mice | Increased fibrosis, Increased sarcomere contraction and disorganized myofibrils | N/A | [41] |
AAC | ||||||
Nppb | Liver-specific human serum amyloid P component promoter-mediated BNP plasma OE | MI | 8–12 weeks/mice | Increased neutrophile infiltration in the infracted area and increased cardiac MMP-9 expression | N/A | [42] |
Nppb, Npr1 | Global KO Nppb Global KO Npr1 | TAC + FAP inhibition | 8–10 weeks | Decreased fibrosis, improved cardiac function, increased angiogenesis in BNP+/+ and NPRA+/+ | Fap inhibition results in BNP/NPRA-mediated cardioprotection | [43] |
MI + FAP inhibition | ||||||
Proliferation | ||||||
NPs or NP receptors | Experimental model | Manipulation | Age/species | Intracardiac observations | Proposed pathways | Ref. |
Npr1 | Global KO | None | P2/mice | Increase in CM number | N/A | [44] |
CM-specific KO | None | No difference | ||||
ANP | None | Intracardiac ANP + MI | Neonatal (ND7)/mice | No difference observed compared to control littermates | ANP, BNP/NPRC signaling and FOXO nuclear activity cooperatively regulate CM cell cycle activity | [45] |
Intracardiac ANP + DN-FOXO + MI | Reactivation of CM cell cycle, reduced scar formation | |||||
BNP | None | Bidaily BNP IP injection | Neonatal mice | Increased number of CMs, increase in CM cell cycle re-entry | BNP activation of the MAPK/ERK pathway | [46] |
None | Bidaily BNP IP injection+MI | 8 weeks/mice | Increased number of CMs, increase in CM cell cycle re-entry, decreased apoptosis | |||
Myh6 MerCreMer (tamoxifen -D14) | Bidaily BNP IP injection+MI | Increase in TNTI+/GFP+ cells, increase in CM cell cycle re-entry | ||||
Npr1−/− | Bidaily BNP IP injection | Unchanged number of CMs | ||||
None | Inhibitor of BNP degradation (LCZ696) + MI | Increased number of CMs, increase in CM cell cycle re-entry | ||||
Metabolism and autophagy | ||||||
NPs or NP receptors | Experimental model | Manipulation | Age/species | Intracardiac observations | Proposed pathways | Ref. |
Npr1 | CM specific KO | None | Not described/mice | Increase in metabolic processes | circRNA and microRNA | [47] |
Npr1 | CM specific KO | None | 8 weeks/mice | Metabolic deregulation | Positive enrichment in nucleotide synthesis and histidine metabolism, negative enrichment of mitochondrial proteins | [48] |
Nppa | Global KO | Nppa−/− + I/R | 8–10 weeks/mice | Increased infarct size and reduced autophagy | ANP/NPR1/PRKG-mediated stimulation of autophagy through activation of TFEB | [38] |
ANP | Embryonic ventricular cell cultures | ANP treatment | E11.5/mice | Increased VCS cell proliferation | ANP/NPRA-mediated increase in PPARG and FAO promotes VCS formation | [49] |
ANP | Primary cardiomyocyte cultures | ANP treatment | Adult/rats | Reduced cardiomyocyte apoptosis | ANP- and CNP-mediated DrpI phosphorylation and caspase 9 decrease | [50] |
CNP | CNP treatment | |||||
BNP | No genetic modification | 4 weeks of BNP administration 7 days after STZ-induced diabetic cardiomyopathy | 8 weeks/mice | Preservation of mitochondrial function and prevention of DMC onset | BNP/NPRA/PKG/STAT3-OPA1-mediated mitochondrial fusion activation | [51] |
AAV9-shBNP after 5 days of STZ-induced diabetic cardiomyopathy | Impaired mitochondrial function, exaggerated cardiac dysfunction | |||||
Electrophysiology | ||||||
NPs or NP receptors | Experimental model | Manipulation | Age/species | Intracardiac observations | Proposed pathways | Ref. |
Npr2 | Global KO (Npr2−/+) | none | 20 weeks/mice | Increased cSNRT, spontaneous AP frequency, slower HR, reduced If and Ica, L currents | NPR-B/cGMP-mediated inhibition of PDE3 | [52] |
Nppa, Nppb | Global KO Nppa−/− or Nppb−/− | none | 1–12 months/mice | Mild ventricular remodeling, no cardiac functional dysfunction | ANP, BNP/cGMP/PKG1/p38MAPK-mediated phophorylation of CREB | [53] |
TAC | ||||||
Isoproterenol treatment | Increased incidence of ventricular arrythmias | |||||
Npr3 | Global KO | None | 10–15 weeks/mice | SAN dysfunction, atrial suspeptibility and increased fibrosis | N/A | [54] |
Npr3 | Global KO | none | 10–15 weeks/mice | SAN dysfunction and increased SAN fibrosis | N/A | [55] |
Ang-II treatment | ||||||
Npr3 | Global KO | none | 10–15 weeks/mice | Atrial suspeptibility and increased atrial fibrosis | N/A | [56] |
Ang-II treatment | ||||||
Contractility | ||||||
NPs or NP receptors | Experimental model | Manipulation | Age/species | Intracardiac observations | Proposed pathways | Ref. |
Npr2 | CM specific Npr2 KO | TAC | 2 months/mice | Increased ventricular stiffness, LV diastolic and systolic dysfunction | CNP/NPRB/cGMP/PKGI-mediated Ser4080 phosphorylationof Tintin | [57] |
CNP, BNP | cGMP biosensor | Isolated cardiomyocytes | Neonatal-adult/rats | Increased lucitropic and negative inotropic effects by CNP | CNP increases cGMP near TnI and PLB, regulated by PDE2 and PDE3 BNP increases cGMP only near PLB | [58] |
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Giovou, A.E.; Gladka, M.M.; Christoffels, V.M. The Impact of Natriuretic Peptides on Heart Development, Homeostasis, and Disease. Cells 2024, 13, 931. https://doi.org/10.3390/cells13110931
Giovou AE, Gladka MM, Christoffels VM. The Impact of Natriuretic Peptides on Heart Development, Homeostasis, and Disease. Cells. 2024; 13(11):931. https://doi.org/10.3390/cells13110931
Chicago/Turabian StyleGiovou, Alexandra E., Monika M. Gladka, and Vincent M. Christoffels. 2024. "The Impact of Natriuretic Peptides on Heart Development, Homeostasis, and Disease" Cells 13, no. 11: 931. https://doi.org/10.3390/cells13110931