Characterization and Functions of Protease-Activated Receptor 2 in Obesity, Diabetes, and Metabolic Syndrome: A Systematic Review
Table 1
PAR2 in obesity, diabetes, and metabolic syndrome: blood vessel function studies.
Model
Species
Sex
Strain
Age (weeks)
Metabolic phenotype
Vessel
PAR2 effects on blood vessels with endothelial dysfunction
PAR reagents
Article
Notes
Glucose
Insulin
Body mass
Nonobese diabetic (type 1 diabetes)
Mouse
F
NOD
5 13 22
Low High Severe
nd
Similar to control
Aorta
PAR2 dilation preserved by endothelial cell-independent mechanism. PAR2 de novo induction in vascular smooth muscle cells. COX-1 activity increased in vascular smooth muscle cells
Mean ages are listed; NOD/ mice separated into groups by urinary glucose levels: low (0–20 mg/dL), high (20–500 mg/dL), severe 500–1000 mg/dL; CD-1 mice used as age-matched controls for body weight, data were not shown
Nonobese diabetic (type 2 diabetes)
Rat
M
Goto-Kakizaki
32–40
2.5 times control
1.6 times control
0.75 times control
Superior-mesenteric artery
PAR2 vasodilation sensitivity increased/preserved by endothelial cell PAR2-nitric oxide pathway
Male TallyHo mice were reported as being hyperglycemic by Li et al. [48], but glucose, insulin, and body mass data were not shown. Phenotype data in Table 1 are from a separate study led by the same investigators [49]. Lean control (C57B6) and PAR2 knockout mice were age-matched to TallyHo mice. Control [49] (16 weeks of age) mean values: nonfasting blood glucose, 12.2 mM; serum insulin 0.8 µg/g; body mass, 33 g. RT-PCR data provided evidence of PAR2 mRNA in adipocytes dissociated by collagenase treatment from perivascular aorta and mesenteric adipose tissue
Obese diabetic (type 2 diabetes)
Mouse
M
db/db
12–16
3 times control
nd
1.7 times control
Coronary microvessels
PAR2-AP vasodilation in vitro increased PAR2 antagonist treatment in vivo reduced endothelial dysfunction
PAR2-AP: 2fLIGRLO; control AP: 2fOLRGIL; PAR2 “putative” antagonist (in vivo) FSLLRY
Control (C57BL6) mean values for blood glucose, 156 mg/dL; body weight, 27 g. TNF knockdown mice crossed with db/db mice also were tested; no effect of FSLLRY-amide peptide on metabolic phenotype. Experiments were conducted using pressurized blood vessel assay
Obese diabetic (type 2 diabetes)
Mouse
M
db/db
12
2 times control
30 times control
2 times control
Second-order mesenteric artery
PAR2 vasodilation preserved by endothelium-dependent hyperpolarization factor
Control (C57BL/6 age-matched) mean values for blood glucose, 11 mM; urinary glucose in db/db > 55 mM versus below assay detection limit (2 mM); serum insulin, 1.13 ng/mL; body mass, 27.5 g
Metabolic syndrome
Rat
M
SHRSP.Z-Leprfa.lz mDmcr (MetS)
13, 16, 23
1.7 times control
12.5 times control
1.2 times control
Superior and first-order branch mesenteric arteries
Preserved PAR2-mediated dilation by increased NO synthase contribution in MetS
Control (Wistar) mean values at 18 weeks of age: urine glucose, 187 mg/100 mL; serum insulin, 3.11 ng/mL; weights, 405 g; serum triglycerides, 46 mg/100 mL. MetS rats showed intolerance to elevation of blood glucose after oral glucose challenge. Systolic blood pressures (tail-cuff method) in MetS group were 60% higher than Wistar (110 mmHg) and decreased by administering in vivo telmisartan
Control (lean age-matched chow) mean values at nonfasting plasma glucose, 10 mM; body weights, 590 g. HFD (16–20 weeks treatment period) contained 2 times caloric content of chow diet. Retroperitoneal fat mass increased by 2.9-times (1.4% of body mass in control)
nd: variables were not determined; PAR2 activating and control peptides are identified by their amino acid sequences using the standard capitalized one-letter abbreviations. All peptides were synthesized as amides. Sequences starting with 2f indicate N-terminal modification with a 2-furoyl functional group.
