EN
Homoarginine-modulated spatially distinct cGMP pools as novel targets for heart failure (RP7)
Principial Investigators
Project Summary and Goals
Both, cAMP and cGMP play a central role in cardiomyocyte (CM) physiology. Several cAMP and cGMP microdomains have been identified in CMs, compartmentalized by the origin and degradation of these second messengers. In our previous work, we identified low homoarginine (hArg) as an independent predictor of morbidity and mortality in heart failure with reduced ejection fraction (HFrEF) patients (Atzler et al. 2013). L-Arginine:glycine amidinotransferase (AGAT) knock-out mice showed hArg and creatine deficiencies, leading to ventricular dysfunction, while hArg supplementation rescued the impaired cardiac contractility and relaxation under β-adrenergic stimulation (Atzler et al. 2017). Moreover, increased cAMP levels after β-adrenergic stimulation may lead to morphological and functional defects (Kamel et al. 2023), whereas elevated cGMP levels can be cardioprotective (Bork et al. 2021). Excitingly, we could also show that hArg could convey cardioprotection not only in HFrEF but also in a heart failure with preserved ejection fraction (HFpEF) animal model (Büttner et al. 2021).
Aims Addressed by the Doctoral Candidates
- Analysis of biomarkers including hArg in cardiovascular patient cohorts and mouse models of HFpEF. In mouse cardiomyocytes, contractility/relaxation measurements will be performed and local PDE activities and cGMP targets will be analyzed.
- Evaluate microdomain-specific molecular mechanisms of β-blocker effects in isolated healthy and HFpEF mouse and human myocytes by cutting-edge live cell imaging, functional and biochemical assays.
Key Techniques
- Cohort studies of patients with cardiovascular disease
- Animal models of heart failure
- Echocardiography
- Biomarker analysis with ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS)
- Förster resonance energy transfer (FRET) biosensors and microscopy
- Cardiomyocyte contractility and calcium transient measurements
- Patch-Clamp
Publications
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Dietary Supplementation with Homoarginine Preserves Cardiac Function in a Murine Model of Post-Myocardial Infarction Heart Failure. Atzler D, McAndrew DJ, Cordts K, Schneider JE, Zervou S, Schwedhelm E, Neubauer S, Lygate CA (2017). Circulation. 135:400-402. -
Homoarginine - an independent marker of mortality in heart failure. Atzler D, Rosenberg M, Anderssohn M, Choe CU, Lutz M, Zugck C, Böger RH, Frey N, Schwedhelm E (2013). Int J Cardiol. 168:4907-4909. -
Rise of cGMP by partial phosphodiesterase-3A degradation enhances cardioprotection during hypoxia. Bork NI, Kuret A, Cruz Santos M, Molina CE, Reiter B, Reichenspurner H, Friebe A, Skryabin BV, Rozhdestvensky TS, Kuhn M, Lukowski R, Nikolaev VO (2021). Redox Biol. 48:102179. -
Arginine metabolism and nitric oxide turnover in the ZSF1 animal model for heart failure with preserved ejection fraction. Büttner P, Werner S, Baskal S, Tsikas D, Adams V, Lurz P, Besler C, Knauth S, Bahls M, Schwedhelm E, Thiele H (2021). Sci Rep. 11:20684. -
Cyclic nucleotide phosphodiesterases as therapeutic targets in cardiac hypertrophy and heart failure. Kamel R, Leroy J, Vandecasteele G, Fischmeister R (2023). Nat Rev Cardiol. 20:90-108. -
Cardiac gene therapy with Phosphodiesterase 2A limits remodeling and arrhythmias in Mouse Models of Heart Failure. Kamel R, Bourcier A, Margaria JP, Jin V, Varin A, Hivonnait A, Mercier-Nomé F, Mika D, Ghigo A, Charpentier F, Algalarrondo V, Hirsch E, Fischmeister R, Vandecasteele G, Leroy J (2025). J Am Heart Assoc. 14:e037343.