Non-classical RAAS components

Non-classical RAAS - The Counter-Regulatory Axis

• Central enzyme: Angiotensin-Converting Enzyme 2 (ACE2).
• ACE2 counters the classical pathway by converting Angiotensin II → Angiotensin-(1-7).
• Ang-(1-7) binds to the Mas receptor, promoting:
  • Vasodilation
  • Anti-inflammatory effects
  • Anti-fibrosis
  • Natriuresis

⭐ ACE2 is the functional receptor for the SARS-CoV-2 virus, providing its entry point into cells.

Key Players - ACE2, Ang-(1-7) & Mas Receptor

• Angiotensin-Converting Enzyme 2 (ACE2):

  • A key enzyme of the protective RAAS axis; counter-regulates classical RAAS.
  • Primarily metabolizes Angiotensin II → Angiotensin-(1-7), thus inactivating the potent vasoconstrictor.
  • Also converts Angiotensin I → Angiotensin-(1-9).
  • Its actions result in net vasodilation and anti-proliferative effects.

• Angiotensin-(1-7) [Ang-(1-7)]:

  • The main effector peptide of the counter-regulatory pathway.
  • Mediates biological functions opposite to Angiotensin II:
    • ↑ Vasodilation (stimulates nitric oxide synthase)
    • ↓ Fibrosis & cellular proliferation
    • ↓ Inflammation & thrombosis

• Mas Receptor (MasR):

  • A specific G-protein coupled receptor for Ang-(1-7).
  • Binding of Ang-(1-7) to MasR mediates most of its protective cardiovascular and renal effects.

⭐ High-Yield: ACE2 serves as the primary cellular entry receptor for the SARS-CoV-2 virus.

Cardioprotective Effects - The Good Guys' Actions

The non-classical RAAS pathway counteracts the harmful effects of the classical pathway, primarily through Angiotensin-(1-7) and its receptor, Mas.

• Key Players & Actions:
  • ACE2 (Angiotensin-Converting Enzyme 2): Converts Angiotensin II → Angiotensin-(1-7).
  • Ang-(1-7) via Mas Receptor (MasR):
    • Vasodilation: ↑ Nitric Oxide & prostaglandins → ↓ Blood Pressure.
    • Anti-proliferative: Halts smooth muscle & fibroblast growth.
    • Anti-hypertrophic: Prevents cardiac muscle enlargement.
    • Anti-fibrotic: Reduces collagen deposition in the heart & kidneys.
  • Angiotensin-(1-9) via AT2 Receptor (AT2R): Also contributes to similar protective effects.

⭐ High-Yield: ACE inhibitors (e.g., lisinopril) and ARBs (e.g., losartan) can indirectly boost this protective pathway by increasing the substrate available for enzymes like ACE2, enhancing the production of Ang-(1-7).

High‑Yield Points - ⚡ Biggest Takeaways

• The non-classical RAAS provides a crucial counter-regulatory arm to the classical pathway, promoting balance.
• ACE2 is the central enzyme, converting Angiotensin II to the beneficial peptide Angiotensin-(1-7).
• Ang-(1-7) acts on the Mas receptor to mediate vasodilation, anti-inflammatory, and anti-fibrotic effects.
• This pathway's actions directly oppose the vasoconstrictive and pro-fibrotic effects of Angiotensin II via the AT1 receptor.
• ACE2 is also the functional receptor for the SARS-CoV-2 virus.