Hypertension and insulin resistance: Role of peroxisome proliferator-activated receptor gamma

1. Insulin resistance has been highlighted as a common causal factor for hy pertension, hyperlipidaemia, diabetes mellitus and obesity, all of which ar e recognized to occur simultaneously; and a distinct clinical entity is def ined as 'multiple risk factor syndrome'. 2. Recently, a new class of antidiabetic agents, thiazolidinediones (TZD) h as been developed and has been shown to improve insulin resistance by bindi ng and activating a nuclear receptor, peroxisome proliferator-activated rec eptor (PPAR)gamma. 3. cDNA of rat PPAR gamma 1 and gamma 2 were cloned and gene regulation of PPAR gamma in rat mature adipocytes was examined, Hydrogen peroxide, an oxy gen radical, which is recognized to be the common intracellular signal for multiple risk factors, potently down-regulated PPAR gamma mRNA expression i n rat mature adipocytes. 4. Tumour necrosis factor (TNF)-alpha, which is considered to play a role i n obesity-induced non-insulin-dependent diabetes mellitus and to augment ox idative stress, also suppressed PPAR gamma expression 5. Thiazolidinediones dose-dependently recovered TNF-alpha-induced down-reg ulation of PPAR gamma mRNA expression, 6. The modulation of PPAR gamma expression by TZD can he one mechanism for the improvement of insulin resistance by TZD, 7. Vascular tone and remodelling are controlled by several vasoactive autoc rine/paracrine factors produced by endothelial cells in response to several vascular injury stimuli, including hypertension. The PPAR gamma gene trans cript was detected in cultured endothelial cells. 8. The administration of TZD stimulated the endothelial secretion of type-C natriuretic peptide, which is one of the natriuretic peptide family and is demonstrated by us to act as a novel endothelium-derived relaxing peptide. 9. Concomitantly, TZD significantly suppressed the secretion of endothelin, a potent endothelium-derived vasoconstricting peptide. 10. Thiazolidinediones can affect vascular tone and growth by modulating th e production of endothelium derived vasoactive substances to influence occu rrence and progression of hypertension and atherosclerosis.