Droplet Digital PCR Is a Novel Screening Method Identifying Potential Cardiac G-Protein-Coupled Receptors as Candidate Pharmacological Targets in a Rat Model of Pressure-Overload-Induced Cardiac Dysfunction

Sayour, Nabil V. [Sayour, Viktor Nabil (farmakológia), author] Department of Pharmacology and Pharmacotherapy (SU / FM / I); HCEMM-SU Cardiometabolic Immunology Research Group (SU / FM / I / DPP); MTA-SE Momentum Cardio-Oncology and Cardioimmun... (SU / FM / I / DPP); Tóth, Viktória É.* [Tóth, Viktória (Farmakológia), author] HCEMM-SU Cardiometabolic Immunology Research Group (SU / FM / I / DPP); MTA-SE Momentum Cardio-Oncology and Cardioimmun... (SU / FM / I / DPP); Nagy, Regina N. [Nagy, Regina Norma (PhD hallgató), author] Department of Pharmacology and Pharmacotherapy (SU / FM / I); Vörös, Imre [Vörös, Imre (Farmakológia), author] Department of Pharmacology and Pharmacotherapy (SU / FM / I); HCEMM-SU Cardiometabolic Immunology Research Group (SU / FM / I / DPP); MTA-SE Momentum Cardio-Oncology and Cardioimmun... (SU / FM / I / DPP); Gergely, Tamás G. [Gergely, Tamás G (kardiovaszkuláris...), author] Department of Pharmacology and Pharmacotherapy (SU / FM / I); HCEMM-SU Cardiometabolic Immunology Research Group (SU / FM / I / DPP); MTA-SE Momentum Cardio-Oncology and Cardioimmun... (SU / FM / I / DPP); Onódi, Zsófia [Onódi, Zsófia (Farmakológia), author] Department of Pharmacology and Pharmacotherapy (SU / FM / I); HCEMM-SU Cardiometabolic Immunology Research Group (SU / FM / I / DPP); MTA-SE Momentum Cardio-Oncology and Cardioimmun... (SU / FM / I / DPP); Nagy, Noémi [Nagy, Noémi (Tumorbiológia), author] Patológiai és Kísérleti Rákkutató Intézet (SU / FM / I); Bödör, Csaba [Bödör, Csaba (Molekuláris Onkoh...), author] Patológiai és Kísérleti Rákkutató Intézet (SU / FM / I); Váradi, Barnabás [Váradi, Barnabás (Farmakológia), author] Department of Pharmacology and Pharmacotherapy (SU / FM / I); HCEMM-SU Cardiometabolic Immunology Research Group (SU / FM / I / DPP); Ruppert, Mihály [Ruppert, Mihály (orvostudomány), author] Department of Cardiology – Heart and Vascular C... (SU / FM / C); Radovits, Tamás [Radovits, Tamás (kardiológia, érgy...), author] Department of Cardiology – Heart and Vascular C... (SU / FM / C); Bleckwedel, Federico; Zelarayán, Laura C.; Pacher, Pal [Pacher, Pál (Kardiovaszkuláris...), author]; Ágg, Bence [Ágg, Bence (Farmakológia), author] Department of Pharmacology and Pharmacotherapy (SU / FM / I); MTA-SE System Pharmacology Research Group (SU / FM / I / DPP); Görbe, Anikó [Görbe, Anikó (orvostudomany), author] Department of Pharmacology and Pharmacotherapy (SU / FM / I); Ferdinandy, Péter [Ferdinandy, Péter (Farmakológia, mol...), author] Department of Pharmacology and Pharmacotherapy (SU / FM / I); MTA-SE System Pharmacology Research Group (SU / FM / I / DPP); Varga, Zoltán V. ✉ [Varga, Zoltán (kardiovaszkuláris...), author] Department of Pharmacology and Pharmacotherapy (SU / FM / I); HCEMM-SU Cardiometabolic Immunology Research Group (SU / FM / I / DPP); MTA-SE Momentum Cardio-Oncology and Cardioimmun... (SU / FM / I / DPP)

English Article (Journal Article) Scientific
Published: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 1661-6596 1422-0067 24 (18) Paper: 13826 , 18 p. 2023
  • SJR Scopus - Inorganic Chemistry: D1
Identifiers
Fundings:
  • Establishing the Hungarian Center of Excellence for Molecular Medicine in partnership with EMBL(739593) Funder: Horizon 2020
  • (LP-2021-14)
  • (RRF-2.3.1-21-2022-00003)
  • (NVKP-16-1-2016-0017 National Heart Program) Funder: NRDIO
  • (2020-4.1.1.-TKP2020)
  • (TKP2021-EGA-23) Funder: Ministry for Innovation and Technology
  • National Research, Development and Innovation Office (NKFIH) of Hungary(K134939)
  • National Research, Development and Innovation Office (NKFIH) of Hungary(FK134751)
  • János Bolyai Research Scholarship of the Hungarian Academy of Sciences
  • (ÚNKP-22-5-SE-20)
  • Az orvos-, egészségtudományi- és gyógyszerészképzés tudományos műhelyeinek fejlesztése(EFOP-3.6.3-VEKOP-16-2017-00009) Funder: EFOP-VEKOP
  • (European Union’s Horizon 2020 Research and Innovation (101007931))
The identification of novel drug targets is needed to improve the outcomes of heart failure (HF). G-protein-coupled receptors (GPCRs) represent the largest family of targets for already approved drugs, thus providing an opportunity for drug repurposing. Here, we aimed (i) to investigate the differential expressions of 288 cardiac GPCRs via droplet digital PCR (ddPCR) and bulk RNA sequencing (RNAseq) in a rat model of left ventricular pressure-overload; (ii) to compare RNAseq findings with those of ddPCR; and (iii) to screen and test for novel, translatable GPCR drug targets in HF. Male Wistar rats subjected to transverse aortic constriction (TAC, n = 5) showed significant systolic dysfunction vs. sham operated animals (SHAM, n = 5) via echocardiography. In TAC vs. SHAM hearts, RNAseq identified 69, and ddPCR identified 27 significantly differentially expressed GPCR mRNAs, 8 of which were identified using both methods, thus showing a correlation between the two methods. Of these, Prostaglandin-F2α-receptor (Ptgfr) was further investigated and localized on cardiomyocytes and fibroblasts in murine hearts via RNA-Scope. Antagonizing Ptgfr via AL-8810 reverted angiotensin-II-induced cardiomyocyte hypertrophy in vitro. In conclusion, using ddPCR as a novel screening method, we were able to identify GPCR targets in HF. We also show that the antagonism of Ptgfr could be a novel target in HF by alleviating cardiomyocyte hypertrophy.
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2025-04-02 03:56