Formyl Peptide Receptor‐1 Activation is Crucial for Spontaneous and Salt‐Induced Hypertension in Dahl Salt Sensitive Rats: Mitochondria vs. Microbiota

Abstract

AimsMitochondria evolved from bacteria and carry the same hallmarks that are an important source of inflammatogenic damage‐associated molecular patterns. One hallmark is the use of N‐formylated peptides (NFPs) as an initiator of protein synthesis. NFPs activate formyl peptide receptor (FPR‐1) and lead to vascular injury. When we first worked with Dahl Salt Sensitive (S) rats model, we observed that Dahl S fed a low‐salt (LS) diet presented signs of vascular dysfunction and spontaneous elevation of BP compared to Dahl Salt Resistant (R) rats. High‐salt (HS) diet worsened the hypertensive phenotype. Intriguingly, we observed that FPR‐1 is upregulated in arteries, and mitochondrial NFPs are elevated in the circulation of S rats (LS). We hypothesized that cell death‐derived mitochondrial NFPs and FPR‐1 activation leads to vascular dysfunction and the genesis of spontaneous elevation of BP in S rats. Because of the dual source of NFPs (from microbiota and host mitochondria), we also hypothesized that HS diet leads to gut barrier disruption, and a synergistic action of mitochondria and bacterial‐derived leaky gut NFPs are the major driving force in the maintenance of hypertension.MethodsMale S and R rats (6‐week old) were given a LS (0.3% NaCl) or HS diet (2% NaCl). Blood pressure (BP) was measured by telemetry. After 3 weeks on LS or HS diets, rats were treated (osmotic mini‐pump) with FPR‐1 antagonist [Cyclosporin H (CsH), 0.3 mg/kg/day, 14 days]. In another group, rats received water with amoxicillin (AMO, 5 mg/kg/day) for 3 weeks to deplete bacteria. Mesenteric resistance arteries (MRA) were collected to assess vascular function via wire myograph. Blood samples were collected to measure zonulin, a leaky gut biomarker via Elisa. t‐test p<0.05 *vs. R; #vs. absence of treatment; n=8–11 for R and S; n=6 for R and S+AMO; n=5–6 for R and S+CsH.Results and ConclusionS rats (LS) have a spontaneous elevation in BP. Treatment with FPR‐1 antagonist (CsH) decreased this response [BP (mmHg): Diastolic: R: 77±2.7 vs. R+CsH: 81±1.2 vs. S: 126±3.0* vs. S+CsH:115±2.7#]. Also, CsH decreased hypercontractility observed in arteries from S LS when compared to R rats [KCl 120mM (mN): R: 9.4±1.0 vs. R+CsH: 10.2±0.4 vs. S: 15.5±0.9* vs. S+CsH:11.7±0.8#). This suggests that FPR‐1 serves as a causative agent to the spontaneous elevation of BP. AMO did not decrease BP in S‐LS diet [BP (mmHg): Diastolic: R: 77±2.7 vs. R+AMO: 82±2.7 vs. S: 126±3.0* vs. S+CsH: 124±1.3]. In addition, zonulin is not increased in plasma in S‐LS, suggesting that leaky gut is not associated with spontaneous elevation of BP in S‐LS. However, zonulin is increased in plasma during HS diet (severe hypertension) [Zonulin (ng/mL): R‐LS: 4.09±0.1 vs. S‐LS: 4.01±0.3 vs. R‐HS: 4.31±0.1 vs. S‐HS: 6.3±0.2#]. Overall, FPR‐1 activation due to increased levels of mitochondrial NFPs is associated with the genesis of spontaneous elevations of BP in Dahl S rats. High‐salt diet leads to gut barrier disruption and, subsequently, a synergistic action of mitochondria and bacterial‐derived leaky gut NFPs are the major driving force in the maintenance of hypertension.Support or Funding InformationNSF AGEP:1432878, NIH:R00GM118885, AHA:18POST34060003