Abstract P108: A Novel Target For CVD Treatment: The Adipokine Chemerin Drives Hypertensive Blood Pressure And Potentially Aortic Stiffening In Female Dahl SS Rats

Chemerin, an inflammatory adipokine, supports basal blood pressure in male and female Dahl SS rats and, to a greater degree, adiposity-associated hypertensive blood pressure in the male rat, evidenced by falls in mean arterial pressure following an antisense oligonucleotide (ASO)-mediated loss of chemerin protein. Liver-specific ASOs that abolished hepatic-derived chemerin yielded no change in blood pressure; thus, it must be extra-hepatic chemerin that supports blood pressure. Our current focus is investigating the role of vascular chemerin—that produced by the blood vessel and its perivascular adipose tissue (PVAT)—in adiposity-associated hypertension and cardiovascular disease (CVD) development. We hypothesized that male Dahl SS rats would be more dependent on chemerin for hypertensive blood pressure because male rats gain more visceral fat (and likely more PVAT) than females on a high-fat diet. Age-matched female Dahl SS rats on a control or high fat (60%) diet from weaning were used. Radiotelemeters were implanted to measure blood pressure (MAP). Acute knockout of chemerin was achieved by subcutaneous injection of whole-body ASO against chemerin or PBS (25 mg/kg) on days 0, 7, 14, and 21. On day 23, the rats were euthanized, and tensile tests were performed on isolated thoracic aortae. Chemerin mRNA (2 - ΔCT ) was significantly reduced in the liver (C: 0.56 ± 0.07, ASO: 0.00 ± 0.00) and thoracic aorta (C: 0.03 ± 0.01, ASO: 0.00 ± 0.00). MAP in PBS rats had no significant change from baseline measurements (C:159.0 ± 7.5, HF: 170.2 ± 3.4 mmHg), while control and HF-diet females treated with ASO dropped 14.0 ± 1.2 and 28.5 ± 4.2 mmHg, respectively, after four injections. Pulse pressure also decreased 3.4 ± 1.1 and 6.8 ± 0.8 mmHg in ASO-treated control and HF females, respectively. Interestingly, localized vessel stiffness was modestly lower in ASO-treated vs PBS animals on control diet (PBS: 174.2 ± 14.2 ASO: 151.4 ± 24.2 kPa; N=4/group). These data suggest that chemerin plays a similar role in driving adiposity-associated hypertensive blood pressure in males and females; additionally, chemerin may be a blood pressure-independent risk factor for aortic stiffness. Future work aims to further uncover chemerin’s potential as a therapeutic target for CVD treatment.