Hypertension and insulin resistance: role of peroxisome proliferator-activated receptor gamma.
1. Insulin resistance has been highlighted as a common causal factor for hypertension, hyperlipidaemia, diabetes mellitus and obesity, all of which are recognized to occur simultaneously, and a distinct clinical entity is defined as 'multiple risk factor syndrome'. 2. Recently, a new class of antidiabetic agents, thiazolidinediones (TZD) has been developed and has been shown to improve insulin resistance by binding and activating a nuclear receptor, peroxisome proliferator-activated receptor (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 oxygen radical, which is recognized to be the common intracellular signal for multiple risk factors, potently down-regulated PPAR gamma mRNA expression in rat mature adipocytes. 4. Tumour necrosis factor (TNF)-alpha, which is considered to play a role in obesity-induced non-insulin-dependent diabetes mellitus and to augment oxidative stress, also suppressed PPAR gamma expression. 5. Thiazolidinediones dose-dependently recovered TNF-alpha-induced down-regulation of PPAR gamma mRNA expression. 6. The modulation of PPAR gamma expression by TZD can be one mechanism for the improvement of insulin resistance by TZD. 7. Vascular tone and remodelling are controlled by several vasoactive autocrine/paracrine factors produced by endothelial cells in response to several vascular injury stimuli, including hypertension. The PPAR gamma gene transcript 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 the production of endothelium-derived vasoactive substances to influence occurrence and progression of hypertension and atherosclerosis.
Itoh
H
H
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Japan. hiito@kuhp.kyoto-u.ac.jp
Doi
K
K
Tanaka
T
T
Fukunaga
Y
Y
Hosoda
K
K
Inoue
G
G
Nishimura
H
H
Yoshimasa
Y
Y
Yamori
Y
Y
Nakao
K
K
D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000818:Animals; D004822:Epididymis / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007333:Insulin Resistance; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009928:Organ Specificity; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D014157:Transcription Factors