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Serine Carboxypeptidase SCPEP1 and Cathepsin A Play Complementary Roles in Regulation of Vasoconstriction via Inactivation of Endothelin-1


The potent vasoconstrictor peptides, endothelin 1 (ET-1) and angiotensin II control adaptation of blood vessels to fluctuations of blood pressure. Previously we have shown that the circulating level of ET-1 is regulated through its proteolytic cleavage by secreted serine carboxypeptidase, cathepsin A (CathA). However, genetically-modified mouse expressing catalytically inactive CathA S190A mutant retained about 10–15% of the carboxypeptidase activity against ET-1 in its tissues suggesting a presence of parallel/redundant catabolic pathway(s). In the current work we provide direct evidence that the enzyme, which complements CathA action towards ET-1 is a retinoid-inducible lysosomal serine carboxypeptidase 1 (Scpep1), a CathA homolog with previously unknown biological function. We generated a mouse strain devoid of both CathA and Scpep1 activities (DD mice) and found that in response to high-salt diet and systemic injections of ET-1 these animals showed significantly increased blood pressure as compared to wild type mice or those with single deficiencies of CathA or Scpep1. We also found that the reactivity of mesenteric arteries from DD mice towards ET-1 was significantly higher than that for all other groups of mice. The DD mice had a reduced degradation rate of ET-1 in the blood whereas their cultured arterial vascular smooth muscle cells showed increased ET-1-dependent phosphorylation of myosin light chain 2. Together, our results define the biological role of mammalian serine carboxypeptidase Scpep1 and suggest that Scpep1 and CathA together participate in the control of ET-1 regulation of vascular tone and hemodynamics.


Vyšlo v časopise: Serine Carboxypeptidase SCPEP1 and Cathepsin A Play Complementary Roles in Regulation of Vasoconstriction via Inactivation of Endothelin-1. PLoS Genet 10(2): e32767. doi:10.1371/journal.pgen.1004146
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004146

Souhrn

The potent vasoconstrictor peptides, endothelin 1 (ET-1) and angiotensin II control adaptation of blood vessels to fluctuations of blood pressure. Previously we have shown that the circulating level of ET-1 is regulated through its proteolytic cleavage by secreted serine carboxypeptidase, cathepsin A (CathA). However, genetically-modified mouse expressing catalytically inactive CathA S190A mutant retained about 10–15% of the carboxypeptidase activity against ET-1 in its tissues suggesting a presence of parallel/redundant catabolic pathway(s). In the current work we provide direct evidence that the enzyme, which complements CathA action towards ET-1 is a retinoid-inducible lysosomal serine carboxypeptidase 1 (Scpep1), a CathA homolog with previously unknown biological function. We generated a mouse strain devoid of both CathA and Scpep1 activities (DD mice) and found that in response to high-salt diet and systemic injections of ET-1 these animals showed significantly increased blood pressure as compared to wild type mice or those with single deficiencies of CathA or Scpep1. We also found that the reactivity of mesenteric arteries from DD mice towards ET-1 was significantly higher than that for all other groups of mice. The DD mice had a reduced degradation rate of ET-1 in the blood whereas their cultured arterial vascular smooth muscle cells showed increased ET-1-dependent phosphorylation of myosin light chain 2. Together, our results define the biological role of mammalian serine carboxypeptidase Scpep1 and suggest that Scpep1 and CathA together participate in the control of ET-1 regulation of vascular tone and hemodynamics.


Zdroje

1. YanagisawaM, MasakiT (1989) Molecular biology and biochemistry of the endothelins. Trends Pharmacol Sci 10: 374–378.

2. MorishitaR, HigakiJ, OgiharaT (1989) Endothelin stimulates aldosterone biosynthesis by dispersed rabbit adreno-capsular cells. Biochem Biophys Res Commun 160: 628–632.

3. GoracaA (2002) New views on the role of endothelin (minireview). Endocr Regul 36: 161–167.

4. KuriharaY, KuriharaH, SuzukiH, KodamaT, MaemuraK, et al. (1994) Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1. Nature 368: 703–710.

5. HocherB, SchwarzA, FaganKA, Thone-ReinekeC, El-HagK, et al. (2000) Pulmonary fibrosis and chronic lung inflammation in ET-1 transgenic mice. Am J Respir Cell Mol Biol 23: 19–26.

6. AmiriF, VirdisA, NevesMF, IglarzM, SeidahNG, et al. (2004) Endothelium-restricted overexpression of human endothelin-1 causes vascular remodeling and endothelial dysfunction. Circulation 110: 2233–2240.

7. MorrellNW, UptonPD, HighamMA, YacoubMH, PolakJM, et al. (1998) Angiotensin II stimulates proliferation of human pulmonary artery smooth muscle cells via the AT1 receptor. Chest 114: 90S–91S.

8. XuD, EmotoN, GiaidA, SlaughterC, KawS, et al. (1994) ECE-1: a membrane-bound metalloprotease that catalyzes the proteolytic activation of big endothelin-1. Cell 78: 473–485.

9. TurnerAJ, MurphyLJ (1996) Molecular pharmacology of endothelin converting enzymes. Biochem Pharmacol 51: 91–102.

10. ThompsonJS, MoriceAH (1996) Neutral endopeptidase inhibitors and the pulmonary circulation. Gen Pharmacol 27: 581–585.

11. WinterRJ, ZhaoL, KrauszT, HughesJM (1991) Neutral endopeptidase 24.11 inhibition reduces pulmonary vascular remodeling in rats exposed to chronic hypoxia. Am Rev Respir Dis 144: 1342–1346.

12. Pshezhetsky AV (2004) Lysosomal carboxypeptidase. In: Barrett AJ, Rawlings ND, Woessner JF, editors. Handbook of Proteolytic Enzymes. 2nd. ed. London, UK. pp. 1923–1929.

13. HannaWL, TurbovJM, JackmanHL, TanF, FroelichCJ (1994) Dominant chymotrypsin-like esterase activity in human lymphocyte granules is mediated by the serine carboxypeptidase called cathepsin A-like protective protein. J Immunol 153: 4663–4672.

14. ItohK, KaseR, ShimmotoM, SatakeA, SakurabaH, et al. (1995) Protective protein as an endogenous endothelin degradation enzyme in human tissues. J Biol Chem 270: 515–518.

15. MillerJJ, ChangarisDG, LevyRS (1988) Conversion of angiotensin I to angiotensin II by cathepsin A isoenzymes of porcine kidney. Biochem Biophys Res Commun 154: 1122–1129.

16. KokkonenJO, SaarinenJ, KovanenPT (1997) Regulation of local angiotensin II formation in the human heart in the presence of interstitial fluid. Inhibition of chymase by protease inhibitors of interstitial fluid and of angiotensin-converting enzyme by Ang-(1–9) formed by heart carboxypeptidase A-like activity. Circulation 95: 1455–1463.

17. JackmanHL, MassadMG, SekosanM, TanF, BrovkovychV, et al. (2002) Angiotensin 1–9 and 1–7 release in human heart: role of cathepsin A. Hypertension 39: 976–981.

18. SeyrantepeV, HinekA, PengJ, FedjaevM, ErnestS, et al. (2008) Enzymatic activity of lysosomal carboxypeptidase (cathepsin) A is required for proper elastic fiber formation and inactivation of endothelin-1. Circulation 117: 1973–1981.

19. KollmannK, DammeM, DeuschlF, KahleJ, D'HoogeR, et al. (2009) Molecular characterization and gene disruption of mouse lysosomal putative serine carboxypeptidase 1. FEBS J 276: 1356–1369.

20. DengAY, MartinLL, BalwierczakJL, JengAY (1994) Purification and characterization of an endothelin degradation enzyme from rat kidney. J Biochem 115: 120–125.

21. WangY, ZhengXR, RiddickN, BrydenM, BaurW, et al. (2009) ROCK isoform regulation of myosin phosphatase and contractility in vascular smooth muscle cells. Circ Res 104: 531–540.

22. LimaVV, GiachiniFR, CarneiroFS, CarvalhoMH, FortesZB, et al. (2011) O-GlcNAcylation contributes to the vascular effects of ET-1 via activation of the RhoA/Rho-kinase pathway. Cardiovasc Res 89: 614–622.

23. WynneBM, ChiaoCW, WebbRC (2009) Vascular Smooth Muscle Cell Signaling Mechanisms for Contraction to Angiotensin II and Endothelin-1. J Am Soc Hypertens 3: 84–95.

24. BudzynK, MarleyPD, SobeyCG (2006) Targeting Rho and Rho-kinase in the treatment of cardiovascular disease. Trends Pharmacol Sci 27: 97–104.

25. ChenJ, StrebJW, MaltbyKM, KitchenCM, MianoJM (2001) Cloning of a novel retinoid-inducible serine carboxypeptidase from vascular smooth muscle cells. J Biol Chem 276: 34175–34181.

26. KollmannK, MutendaKE, BalleiningerM, EckermannE, von FiguraK, et al. (2005) Identification of novel lysosomal matrix proteins by proteome analysis. Proteomics 5: 3966–3978.

27. LeeTH, ChenJ, MianoJM (2009) Functional characterization of a putative serine carboxypeptidase in vascular smooth muscle cells. Circ Res 105: 271–278.

28. HinekA, RabinovitchM, KeeleyF, Okamura-OhoY, CallahanJ (1993) The 67-kD elastin/laminin-binding protein is related to an enzymatically inactive, alternatively spliced form of beta-galactosidase. J Clin Invest 91: 1198–1205.

29. PriviteraS, ProdyCA, CallahanJW, HinekA (1998) The 67-kDa enzymatically inactive alternatively spliced variant of beta-galactosidase is identical to the elastin/laminin-binding protein. J Biol Chem 273: 6319–6326.

30. RufS, BuningC, SchreuderH, HorstickG, LinzW, et al. (2012) Novel beta-amino acid derivatives as inhibitors of cathepsin A. J Med Chem 55: 7636–7649.

31. NordborgC, KyllermanM, ConradiN, ManssonJE (1997) Early-infantile galactosialidosis with multiple brain infarctions: morphological, neuropathological and neurochemical findings. Acta Neuropathol 93: 24–33.

32. KyllermanM, ManssonJE, WestphalO, ConradiN, NellstromH (1993) Infantile galactosialidosis presenting with congenital adrenal hyperplasia and renal hypertension. Pediatr Neurol 9: 318–322.

33. QinY, ZhouA, BenX, ShenJ, LiangY, et al. (2001) All-trans retinoic acid in pulmonary vascular structural remodeling in rats with pulmonary hypertension induced by monocrotaline. Chin Med J (Engl) 114: 462–465.

34. PrestonIR, TangG, TilanJU, HillNS, SuzukiYJ (2005) Retinoids and pulmonary hypertension. Circulation 111: 782–790.

35. ZhangE, JiangB, YokochiA, MaruyamaJ, MitaniY, et al. (2010) Effect of all-trans-retinoic acid on the development of chronic hypoxia-induced pulmonary hypertension. Circ J 74: 1696–1703.

36. LondheVA, MaisonetTM, LopezB, ShinBC, HuynhJC, et al. (2012) Retinoic Acid Rescues Alveolar Hypoplasia in the Calorie-Restricted Developing Rat Lung. Am J Respir Cell Mol Biol 48 (2) 179–87.

37. LavoieJL, Lake-BruseKD, SigmundCD (2004) Increased blood pressure in transgenic mice expressing both human renin and angiotensinogen in the renal proximal tubule. Am J Physiol Renal Physiol 286: F965–971.

38. GuoDF, ChenierI, LavoieJL, ChanJS, HametP, et al. (2006) Development of hypertension and kidney hypertrophy in transgenic mice overexpressing ARAP1 gene in the kidney. Hypertension 48: 453–459.

39. FalcaoS, SolomonC, MonatC, BerubeJ, GutkowskaJ, et al. (2009) Impact of diet and stress on the development of preeclampsia-like symptoms in p57kip2 mice. Am J Physiol Heart Circ Physiol 296: H119–126.

40. FalcaoS, BisottoS, MichelC, LacasseAA, VaillancourtC, et al. (2010) Exercise training can attenuate preeclampsia-like features in an animal model. J Hypertens 28: 2446–2453.

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