Spirulina and the Renin–Angiotensin System.

The Classical RAS: Renin, ACE, and AngII/AT1R

The classical renin-angiotensin system: angiotensinogen (AGT; 452 aa; α2-globulin; liver; NF-κB-driven acute-phase protein; glucocorticoid-responsive GRE −600 bp; oestrogen ERE −200 bp) is cleaved by renin (aspartyl protease; juxtaglomerular cells; regulated by baroreceptors, macula densa Na&sup+;/Cl−, β1-AR/cAMP; prorenin receptor PRR activates prorenin without cleavage) → angiotensin I (AngI; 10 aa). Angiotensin-converting enzyme (ACE; ACE1; dipeptidyl carboxypeptidase; zinc metalloprotease; His383/His387/Glu411 Zn²&sup+; coordination; pulmonary endothelium > renal; substrate AngI → AngII; also bradykinin → BK(1-7) inactive; BNP; substance P) generates AngII (8 aa; Asp-Arg-Val-Tyr-Ile-His-Pro-Phe). AngII binds AT1R (AGTR1; Gq/Gi-coupled; 7-TM; Tyr292 DRYLAIV motif; β-arrestin desensitisation) → Gq→PLCβ1→IP3/DAG→Ca²&sup+;→vasoconstriction; Gi→cAMP↓; β-arrestin→ERK1/2 biased; NADPH oxidase (Nox1/2/4 assembly via AT1R→Rac1→p47phox→Nox2) → ROS → NF-κB; JAK2→STAT3; epigenetic H3K4me3 at inflammatory loci.

The Counter-regulatory Axis: ACE2, Ang-(1-7), and Mas

ACE2 (ACE2; carboxypeptidase; zinc metalloprotease; His374/His378/Glu402; single-pass type I; 805 aa; broad tissue expression; SARS-CoV-2 receptor via RBD Kd ~15 nM; cleaves AngII → Ang-(1-7) and AngI → Ang-(1-9)) generates Ang-(1-7) (7 aa; Asp-Arg-Val-Tyr-Ile-His-Pro) which binds Mas receptor (Mas1; Gi/Gβγ-coupled; 7-TM; originally G protein coupled receptor labelled oncogene) → eNOS Ser1177 ↑→NO ↑→vasodilation; PKA/Akt ↑→anti-fibrotic, anti-apoptotic; NF-κB ↓ (Mas→Gβγ→PI3K→Akt→IKKβ ↓); antidiuretic (renal tubule Na&sup+; reabsorption ↓ via AngII antagonism). Aldosterone (AngII→adrenal zona glomerulosa→CYP11B2→aldosterone) binds MR/NR3C2 (mineralocorticoid receptor; nuclear; GRE-like HRE; target genes: ENaC α/β/γ subunits; Na&sup+;/K&sup+;-ATPase; NEDD4-2 ubiquitin E3 to ENaC degradation; SGK1 kinase) → renal Na&sup+; retention → BP ↑; aldosterone also drives cardiac/vascular fibrosis via MR→CTGF/fibronectin.

Spirulina ACE-Inhibitory Peptides

Spirulina protein digestion generates a series of small peptides with ACE-inhibitory activity: studies identify Ile-Ala-Pro (IAP; IC50 ~0.1–0.3 mg/mL), Val-Ala-Pro (VAP; IC50 ~0.2–0.5 mg/mL), and Ile-Val-Pro among others. These peptides bind the ACE zinc active site as competitive or non-competitive inhibitors (amino acid residue-specific Zn²&sup+; coordination or C-domain active site occlusion). IC50 values are moderate compared to captopril (IC50 ~0.02 μM), but in vivo, the peptide mixture and food matrix effects produce dose-dependent BP lowering. Phycocyanin hydrolysates additionally contribute ACE-inhibitory peptides (pyrrole-chromophore-bearing peptides with bulky residues fitting ACE S1/S2 subsites).

Spirulina’s Mechanistic Actions

• ACE-inhibitory peptides → AngII ↓: IAP/VAP/IVP GI-digested peptides → ACE competitive inhibition → AngI→AngII conversion ↓ 15–30% in in vitro plasma ACE assays; systolic BP ↓ 4–8 mmHg in hypertensive RCTs (4–8 g/day, 8–12 weeks).
• NF-κB ↓ → AGT/ACE transcription ↓: NF-κB↓→AGT mRNA (acute-phase κB-driven) ↓ 15–25% in hepatocytes; ACE promoter NF-κB element ↓ 10–20%→circulating ACE activity ↓.
• PCB → Nox2 ↓ → AngII-ROS ↓: PCB inhibits Nox2 Rac1-p47phox assembly → AngII-stimulated O&sub2;•− ↓ 30–45% in VSMC (vascular smooth muscle cells)→NF-κB↓→MCP-1/VCAM-1↓→vascular inflammation ↓; ACE2 expression preserved (ROS ↓ reduces shedding of ACE2 ectodomain by ADAM17 → membrane ACE2 ↑).
• Nrf2 → ACE2 ↑ (proposed): Nrf2 activates ACE2 ARE-like element at −2.1 kb of ACE2 promoter (preliminary evidence); ACE2 ↑ 15–25% → AngII→Ang-(1-7) conversion ↑ → Mas receptor → eNOS Ser1177 ↑; anti-inflammatory Mas→Akt→IKKβ↓ loop; also increases airway ACE2 (COVID-19 immunity context debated).
• Aldosterone/MR modulation (indirect): AngII ↓ → adrenal AngII-stimulated aldosterone ↓ (AT1R→CYP11B2 reduced)→MR activation ↓→ENaC/SGK1 ↓→renal Na&sup+; excretion ↑→BP ↓ further; cardiac MR-driven CTGF ↓ 15–25% in spirulina heart failure models.

Clinical Correlates and Dosing

Human RCTs (n=8): 4–8 g/day spirulina for 8–12 weeks → SBP ↓ 4–8 mmHg; DBP ↓ 3–5 mmHg (3 RCTs in hypertensive adults); ACE activity ↓ 10–20% (2 RCTs with direct ACE measurement); Ang-(1-7) ↑ 15–25% (one trial with RAS profiling). Interactions: ACE inhibitors (captopril, lisinopril, enalapril) + spirulina — additive BP lowering; monitor hypotension (especially first-dose effect at >4 g/day spirulina + ACE-I); INR unaffected. ARBs (losartan, valsartan) + spirulina: mechanistically complementary (ARBs block AT1R; spirulina reduces AngII production); monitor BP. K&sup+;-sparing diuretics + spirulina: spirulina provides ~5–12 mg K&sup+;/10g; monitor serum K&sup+; in advanced CKD.