Abstract 100: Interference with Smooth Muscle Peroxisome Proliferator-Activated Receptor-gamma (PPARG) Exacerbates Hypertension and Vascular Dysfunction: Role of TIMP-4

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PPARG, a ligand-activated transcription factor plays a critical role in the regulation of blood pressure and vascular function. We hypothesized that interference of smooth muscle cell (SMC) PPARG exacerbates hypertension (HT) and resistance vessel dysfunction. Transgenic mice expressing dominant negative PPARG (S-P467L) in SMC or non-transgenic controls (NT) were implanted with DOCA pellet and allowed ad libitum access to 0.15 M NaCl for 21 days in addition to regular chow and water. Blood pressure was monitored by telemetry and mesenteric arterial (MA) function was assessed by pressurized myograph. At baseline, 24-hour mean arterial pressure (MAP) was similar between NT and S-P467L mice. DOCA-salt increased MAP to a much greater degree in S-P467L mice (Δ MAP; S-P467L: +34.2±6.0, NT: +13.3±5.7, p<0.05 vs NT). Vasorelaxation to acetylcholine was slightly impaired in S-P467L MA compared to NT at baseline whereas this effect was further exaggerated after DOCA-salt (% relaxation at 10-5 M, S-P467L: 56.1±8.3, NT: 79.4±5.6, p<0.05 vs NT). Vascular morphology at luminal pressure of 75 mmHg showed a significant increase in wall thickness (S-P467L: 18.7±0.8, NT: 16.0±0.4, p<0.05 vs NT) and % media/lumen (S-P467L: 8.4±0.3, NT: 7.1±0.2, p<0.05 vs NT) in S-P467L MA after DOCA-salt. Gene expression profiling in MA revealed a loss of the tissue inhibitor of metalloproteinases (TIMP)-4 in S-P467L compared to NT at baseline (fold change compared to NT; 0.39±0.2, p<0.05). Interestingly, expression of TIMP-4 was significantly increased in MA of NT treated with DOCA-salt compared to NT baseline (1.5±0.1 fold). However, the induction of TIMP-4 was lost in S-P467L with DOCA-salt. There was no difference in mRNA expression of other TIMPs between NT and S-P467L after DOCA-salt. Inhibition of PPARG in primary SMC cultures either by pharmacological inhibitor, GW9662 or mutant PPARG resulted in down-regulation of TIMP-4 expression. Moreover, GW9662 treatment led to an increased total matrix metalloproteinases activity in SMC. We conclude that loss of PPARG function sensitizes the mice to the effects of DOCA-salt induced HT and vascular dysfunction, in part, by preventing the normal protective up-regulation of TIMP-4.