Neprilysin inhibition reduces microtubule detyrosination in cardiomyocytes through a cGMP-PRKG1-VASH1 axis

Q: What is the clinical evidence from this study?

Population: Endothelin-1-induced cardiomyocyte hypertrophy. Intervention: Sacubitrilat vs. Valsartan, combination of sacubitrilat and valsartan, or vehicle (DMSO/sterile H2O). Primary outcome: Detyrosinated α-tubulin (dTyr-tub) level and cellular hypertrophy (cell volume/area).

Q: What does this research mean for the field?

Neprilysin inhibition reduces cardiomyocyte microtubule detyrosination through a cGMP-PRKG1 signaling pathway that phosphorylates and inhibits VASH1. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Moritz Meyer-Jens; Chadni Sanyal; Niels Pietsch; Sacnicte Ramírez‐Ríos; Marisol Herrera-Rivero; Elisabeth Krämer; Ingke Braren; Viacheslav O. Nikolaev; Maike Frye; Saskia Schlossarek; Marie‐Jo Moutin; Lucie Carrier

doi:10.1038/s41598-026-80602-1

November 11, 2026Scientific ReportsOpen Access

Neprilysin inhibition reduces microtubule detyrosination in cardiomyocytes through a cGMP-PRKG1-VASH1 axis

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Key result

Sacubitrilat, unlike valsartan, prevents detyrosinated α-tubulin accumulation in hiPSC-CMs via cGMP-PRKG1-VASH1 signaling.

Why the study?

Elevated levels of detyrosinated alpha-tubulin are observed in heart failure, and whether the active components of the angiotensin receptor-neprilysin inhibitor LCZ696 (sacubitrilat and valsartan) modulate this modification in hypertrophic cardiomyocytes required investigation.

Does neprilysin inhibition with sacubitrilat reduce microtubule detyrosination and cellular hypertrophy in human induced pluripotent stem cell-derived cardiomyocytes?

Key Points

To determine whether the neprilysin inhibitor sacubitrilat modulates microtubule detyrosination in human cardiomyocytes during endothelin-1-induced hypertrophy.
Treated human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) undergoing endothelin-1 (ET1)-induced hypertrophy with sacubitrilat, valsartan, or both.
Evaluated gene expression via RNA sequencing, measured cGMP levels with ELISA and FRET sensor cGi500, and tested pharmacological inhibition (RP-8-Br-PET-cGMPS) or siRNA knockdown of PRKG1.
Assessed detyrosinated α-tubulin levels in hiPSC-CM knockout lines (SVBP-KO and TTL-KO) and tested in vitro phosphorylation of VASH1 mutants (VASH1-7E and VASH1-7A).
ET1 induced a 2.5-fold increase in hiPSC-CM cell volume and a >1.5-fold increase in detyrosinated α-tubulin; sacubitrilat prevented both, whereas valsartan prevented volume expansion but not detyrosinated α-tubulin accumulation.
Sacubitrilat elevated intracellular cGMP levels by about 2-fold, increased the CFP/YFP ratio by about 60% in FRET assays, and stimulated PRKG1 activity.
Pharmacological inhibition of PRKG1 with RP-8-Br-PET-cGMPS increased detyrosinated α-tubulin by 1.4-fold, while siRNA-mediated knockdown of PRKG1 induced a 25% increase in detyrosinated α-tubulin levels.

Structured PICO

Does neprilysin inhibition with sacubitrilat reduce microtubule detyrosination and cellular hypertrophy in human induced pluripotent stem cell-derived cardiomyocytes?

P

Population

In vitro preclinical study using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) subjected to endothelin-1-induced hypertrophy.

I

Intervention

Sacubitrilat (40 µM), valsartan, or combination (sacubitrilat/valsartan); C-type natriuretic peptide (CNP, 100 nM); RP-8-Br-PET-cGMPS (RP8, PRKG1 inhibitor); siRNA knockdown of PRKG1 (siPRKG1); lentiviral overexpression of YFP-tagged mouse VASH1+SVBP constructs (VASH1-WT, phosphomimetic VASH1-7E, or non-phosphorylatable VASH1-7A).

C

Comparator

Vehicle control (DMSO or sterile H2O), endothelin-1 (100 nM) alone, scrambled siRNA (scr), or unphosphorylatable/wild-type VASH1 constructs.

O

Outcome

Levels of detyrosinated α-tubulin (dTyr-tub) and cardiomyocyte hypertrophy (cell volume and area).surrogate

Limitations

Suboptimal target specificity of small-molecule PRKG1 inhibitors such as RP-8-Br-PET-cGMPS (RP8).
Lack of more specific PRKG1 inhibitors to further substantiate the generated data.
Unclear mechanism for why the combination treatment of sacubitrilat and valsartan did not reduce detyrosinated tubulin levels in ET1-treated hiPSC-CMs.
Clinical studies assessing the impact of LCZ696 or its individual components on detyrosinated tubulin levels in human patients are lacking.
PRKG1 inhibitors including RP-8-Br-PET-cGMPS (RP8) have suboptimal target specificity.
More specific PRKG1 inhibitors are currently lacking to substantiate the findings.
The lack of effect of the combination of sacubitrilat and valsartan on dTyr-tubulin levels in ET1-treated hiPSC-CMs remains unclear.
Clinical studies assessing the impact of LCZ696 or its individual components on dTyr-tub levels in patients are lacking.

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Implication

This preclinical study identifies a novel neprilysin-cGMP-PRKG1-VASH1 signaling axis by which sacubitrilat reduces pathological microtubule detyrosination in cardiomyocytes, providing mechanistic insight into the therapeutic benefits of sacubitril/valsartan in heart failure.

Abstract

Microtubule detyrosination and re-tyrosination on the C-terminus of α-tubulin are mediated by the vasohibin (VASH)-small vasohibin-binding protein (SVBP) complex and tubulin tyrosine ligase (TTL), respectively. Elevated levels of detyrosinated α-tubulin (dTyr-tub) are observed in heart failure, and reducing this modification improves cardiac function, suggesting that heart failure therapies may modulate microtubule detyrosination. We investigated whether sacubitrilat and valsartan, the active components of the angiotensin receptor–neprilysin inhibitor LCZ696, influence dTyr-tub levels in endothelin-1 (ET1)-induced hypertrophy in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). While both sacubitrilat and valsartan prevented hypertrophy, only sacubitrilat prevented ET1-induced dTyr-tub accumulation. Sacubitrilat slightly increased cyclic guanosine 3′,5′-monophosphate (cGMP) levels and lowered dTyr-tub, whereas inhibition or knockdown of the cGMP-dependent protein kinase 1 (PRKG1) increased dTyr-tub. PRKG1 phosphorylated native VASH1 . Incubation of microtubules with the VASH1-SVBP complex containing wild-type VASH1, but not a VASH1 phosphomimic (VASH1-7E) increased detyrosination. Consistently, overexpression of VASH1-7E gave rise to lower dTyr-tub level than overexpression of a non-phosphorylatable form of VASH1 (VASH1-7A) in hiPSC-CMs deficient in VASH1. These findings identify a cGMP–PRKG1–VASH1 signaling axis that reduces microtubule detyrosination in cardiomyocytes.

Discussion

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Cite This Study

Meyer-Jens et al. (2026) studied Endothelin-1-induced cardiomyocyte hypertrophy. Sacubitrilat vs. Valsartan, combination of sacubitrilat and valsartan, or vehicle (DMSO/sterile H2O) was evaluated on Detyrosinated α-tubulin (dTyr-tub) level and cellular hypertrophy (cell volume/area). Sacubitrilat, unlike valsartan, prevented endothelin-1-induced >1.5-fold accumulation of detyrosinated α-tubulin in hiPSC-CMs via a cGMP-PRKG1-VASH1 signaling axis.

synapsesocial.com/papers/6af6545d78c9af7e1faf1782 https://doi.org/10.1038/s41598-026-80602-1

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Neprilysin inhibition reduces microtubule detyrosination in cardiomyocytes through a cGMP-PRKG1-VASH1 axis

Key Points

Structured PICO

Limitations

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Implication

Abstract

Discussion

Cite This Study

Neprilysin inhibition reduces microtubule detyrosination in cardiomyocytes through a cGMP-PRKG1-VASH1 axis

Key Points

Structured PICO

Limitations

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Implication

Abstract

Discussion

Cite This Study

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