Leptin induces vascular smooth muscle cell hypertrophy through angiotensin II- and endothelin-1-dependent mechanisms and mediates stretch-induced hypertrophy.
Various cardiovascular pathologies are associated with vascular smooth muscle cell (VSMC) hypertrophy and elevated plasma leptin levels. We used the rat portal vein (RPV) cultured for three days to investigate the effect of mechanical stretch on autocrine secretion of leptin and the effect of exogenous leptin (3.1 nM) on VSMC. Stretching the RPV significantly up-regulated leptin production by greater than 100-fold and leptin receptor expression by up to 10-fold. In addition, stretch increased tissue weight by 23 +/- 1.3 and 30 +/- 1% (P < 0.05), respectively, in the absence or presence of leptin, although this was significantly attenuated by an antileptin antibody (166 ng/ml). Unstretched RPV weight decreased by 7.5 +/- 1.8% in the absence of leptin, whereas in the presence of leptin, weight increased by 6.5 +/- 1.8% (P < 0.05). VSMC size and [3H]leucine incorporation rates were significantly increased by leptin in stretched and unstretched tissues. Leptin-induced hypertrophy was associated with significant extracellular signal-regulated kinase (ERK1/2) activation as well as increased expression of angiotensinogen, the angiotensin type 1 receptor as well as preproendothelin-1, and the endothelin type A receptor, whereas ERK inhibition or inhibition of either the angiotensin II or endothelin-1 systems at both the synthesis and receptor levels blocked the hypertrophic response. The effects of leptin were also completely blocked by the cholesterol-chelating agent methyl-beta-cyclodextrin. Therefore, our study demonstrates stretch-dependent leptin release and a direct hypertrophic effect of leptin on RPV, the latter likely dependent on intact cholesterol-rich membrane microdomains and locally produced paracrine factors.
Zeidan
Asad
A
Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario N6A 5C1, Canada.
Purdham
Daniel M
DM
Rajapurohitam
Venkatesh
V
Javadov
Sabzali
S
Chakrabarti
Subrata
S
Karmazyn
Morris
M
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D003470:Culture Media / Q000032:analysis; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology*; D006984:Hypertrophy / Q000139:chemically induced; D020738:Leptin / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D009929:Organ Size; D011169:Portal Vein / Q000166:cytology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism; D054411:Receptors, Leptin; D013314:Stress, Mechanical; D015854:Up-Regulation
D003470:Culture Media; D019332:Endothelin-1; D020738:Leptin; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D000804:Angiotensin II