Chemerin is a novel protein with growing recognition in the clinical sphere but limited basic science advancements. Hypertension and obesity have strong positive correlations with chemerin protein levels in the blood and are two diseases of the past decade that have continued to grow at alarming levels. Equipped with the limited knowledge that chemerin can directly stimulate the blood vessel to contract and that chemerin is secreted by the fat, we developed the hypothesis that adiposity-associated hypertension is promoted by the release of chemerin from the mesenteric perivascular adipose tissue (mPVAT; primarily adipocytes). We first interrogated the blood vessel and the mPVAT to determine the mechanistic role of chemerin in each of these two tissue types. In the blood vessel, we isolated primary smooth muscle cells and used calcium flux as an indicator of smooth muscle stimulation. Chemerin stimulated calcium flux in a manner dependent on concentration and chemerin1 (the primary receptor for chemerin on the vasculature). We also used various antagonists and inhibitors of the second messenger system to aggregate a basic profile of the actions of chemerin in the blood vessel. Chemerin not only stimulates direct constriction of the blood vessel but mediates this effect through the smooth muscle of the vessel. Chemerin is a critical protein for the adipogenesis of 3T3-L1 cells. Using a germline knockout of chemerin in the rat, we observed the in vivo role of chemerin in the fat, specifically the mPVAT. Histochemistry and polymerase chain reaction (PCR) revealed that chemerin is in fact vital to adipo- and lipogenesis (already known) but is crucial in a location-dependent manner (novel). Specifically, chemerin knockout limited the adipo- and lipogenesis of the mPVAT but not of the neighboring retroperitoneal fat. To determine the effects of chemerin on blood pressure, we used antisense oligonucleotides (ASOs) to knock down chemerin and radiotelemetry to measure blood pressure and other cardiovascular measures. A whole-body knockdown of chemerin reduced the mean arterial pressure by 7 mmHg in a normal Sprague Dawley (SD) rat and by 30 mmHg in a high-fat (hypertensive) Dahl salt-sensitive rat. Surprisingly, an ASO specific to the liver did not change mean arterial pressure but still abolished plasma circulating levels of chemerin. The liver and the fat are the two largest producers of chemerin. While the liver appears to control plasma chemerin levels, the fat is a primary candidate for the contributions of chemerin to blood pressure. A way of targeting drugs (like the ASO) directly to the fat did not exist so we also sought to develop this technology. Using the adipocyte targeting sequence with 9-arginine tag (ATS-9R) electrostatically bonded to the ASO, we are creating a nanoparticle to deliver the ASO in a fat-specific manner. While the in vivo efficacy of this particle is still to be validated, chemerin remains a protein with considerable potential to effect blood pressure, especially blood pressure precipitated by a high-fat diet. Taken together, these data demonstrate a substantial ability for chemerin to alter blood pressure, propose mechanisms by which the fat and blood vessel may interact, and set the stage for future translational therapeutics using chemerin as a target.
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