ACE Inhibitor Pathway

Angiotensin-converting enzyme, or ACE, is a central component of the renin-angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. ACE inhibitors are of medical use as treatment of cardiovascular diseases.

The pathway is centred around angiotensinogen, its conversion to angiotensin I (Ang I) by renin and the subsequent conversion to angiotensin II (Ang II) by angiotensin converting enzyme1. Ang II activates the angiotensin II receptor type 1 (AGTR1) to induce aldosterone synthesis ultimately increasing blood pressure. ACE, the angiotensin converting enzyme, is mainly tissue bound at the plasma membrane. ACE converts Angiotensin I by the removal of 2 amino acids to angiotensin II. ACE inhibitors target the ACE gene product resulting in downstream reduction of Ang II, therefore decreasing aldosterone secretion. The inhibitors increase bradykinin signaling inducing vasodilation with nitric oxide synthase 3 (NOS3) as well2. Along with ACE inhibitors, angiotensin receptor blockers (ARBs), which target AGTR1on cardiac and vascular cells, also resulting in lower levels of aldosterone and lower blood pressure. ARBs are selective for AGTR1 and do not bind to AGTR2. AGTR2 acts as a counterpart to AGTR1mediated signaling, diminishing potentially harmful effects3.

Angiotensin signaling downstream of AGTR1 can occur through several different pathways, as the receptor binds a variety of other proteins; not all functions for them in AgtII signaling via AGTR1 are yet discovered. Examples are the modulation of intracellular calcium, but also via 12-lipoxygenase, PKC and src kinase family routes.AGTR1 can interact with Jak2 thus prompting the Jak-Stat signaling. Downstream signalling is not fully pictured in this graphic. Atgr1, phosphorylated by PKC or specific GPCR kinases, binds beta-arrestin proteins (Arbb). This promotes receptor internalization or receptor recycling, leading to termination or stimulation of the signal, respectively.

AGTR1 mediated signaling stimulates the synthesis of aldosterone and is the main reason for blood pressure decrease. Calcium stimulates calmodulin dependent protein kinase leading to phosphorylation of transcription factors with a role in aldosterone synthesis and release4. They promote enzymes like hydroxylase cytochrome P450 (CYP11B2) involved in aldosterone biosynthesis. Aldosterone itself binds to the mineralocorticoid receptor NR3C2 resulting in its translocation to the cell nucleus, homodimerization and binding to hormone response elements present in the promoter of genes, crucial for transepithelial sodium transport, like epithelial sodium channel (ENaC) or Na+/K+ pumps. This creates a concentration gradient which results in reabsorption of sodium (Na+) ions and water (which follows sodium) into the blood, and secreting potassium (K+) ions into the urine.


References:

  1. Belova LA, (2000): “Angiotensin II-generating enzymes.”. Biochemistry (Mosc), 65(12): 1337-45 [PMID: 11173502]
  2. Taddei S (2016): “Unraveling the Pivotal Role of Bradykinin in ACE Inhibitor Activity.” Am J Cardiovasc Drugs, 16(5):309-21[PMID: 27260014]
  3. Villela D (2015): "Angiotensin type 2 receptor (AT2R) and receptor Mas: a complex liaison.” Clin Sci, 128(4):227-34 [PMID: 25328009]
  4. Basset MH (2004): “The regulation of aldosterone synthase expression.” Mol Cell endocrinol, 217(1-2):67-74.. [PMID: 15134803]


Angiotensin Signaling

Antigens in this category:
AGT (Angiotensinogen (serpin Peptidase Inhibitor, Clade A, Member 8)): AGT antibodies AGT ELISA Kits AGT Proteins
ACE2 - Angiotensin I Converting Enzyme 2: ACE2 antibodies ACE2 ELISA Kits ACE2 Proteins
ACE - Angiotensin I Converting Enzyme 1: ACE antibodies ACE ELISA Kits ACE Proteins
Ang II - Angiotensin II: Ang II antibodies Ang II ELISA Kits Ang II Proteins
CYP11B2 (Cytochrome P450, Family 11, Subfamily B, Polypeptide 2): CYP11B2 antibodies CYP11B2 ELISA Kits CYP11B2 Proteins

Bradykinin Signaling

Antigens in this category:
NOS3 - ENOS: NOS3 antibodies NOS3 ELISA Kits NOS3 Proteins
NANOS3 (Nanos Homolog 3): NANOS3 antibodies   NANOS3 Proteins
KNG1 - Kininogen 1: KNG1 antibodies KNG1 ELISA Kits KNG1 Proteins

Receptor

Antigens in this category:
ATP6AP2 (ATPase, H+ Transporting, Lysosomal Accessory Protein 2): ATP6AP2 antibodies ATP6AP2 ELISA Kits ATP6AP2 Proteins
NR3C2 (Nuclear Receptor Subfamily 3, Group C, Member 2): NR3C2 antibodies NR3C2 ELISA Kits NR3C2 Proteins
MAS1 (MAS1 Oncogene): MAS1 antibodies MAS1 ELISA Kits MAS1 Proteins
BDKRB2 (Bradykinin Receptor B2): BDKRB2 antibodies BDKRB2 ELISA Kits BDKRB2 Proteins
BDKRB1 (Bradykinin Receptor B1): BDKRB1 antibodies BDKRB1 ELISA Kits BDKRB1 Proteins
AGTR2 - Angiotensin II Type 2 Receptor: AGTR2 antibodies AGTR2 ELISA Kits AGTR2 Proteins
AGTR1a (Angiotensin II Receptor, Type 1a): AGTR1a antibodies    
AGTR1 - Angiotensin II Type-1 Receptor: AGTR1 antibodies AGTR1 ELISA Kits AGTR1 Proteins

Serine proteases

Antigens in this category:
CTSG - Cathepsin G: CTSG antibodies CTSG ELISA Kits CTSG Proteins
CMA1 (Chymase 1, Mast Cell): CMA1 antibodies CMA1 ELISA Kits CMA1 Proteins
TNN - Tenascin N: TNN antibodies TNN ELISA Kits  
REN - Renin: REN antibodies REN ELISA Kits REN Proteins
REN1 (Renin 1 Structural): REN1 antibodies REN1 ELISA Kits