Butyrate inhibits proliferation-induced proliferating cell nuclear antigenexpression (PCNA) in rat vascular smooth muscle cells

Arterial injury-induced vascular smooth muscle cell (VSMC) proliferation in intima is the important etiologic factor in vascular proliferative disorde rs such as atherosclerosis, hypertension and restenosis after balloon angio plasty. Butyrate, a naturally occurring short chain fatty acid, is produced by bacterial fermentation of dietary fiber and by mammary glands of certai n mammals. Studies have shown that butyrate at millimolar concentrations, w hich are physiological, induces growth arrest, differentiation and apoptosi s. We examined the effect of physiological concentrations of butyrate on ra t VSMC proliferation and proliferation-induced PCNA expression to determine anti-atherogenic potential of butyrate. Butyrate concentrations, closer to physiological range, exhibited antiproliferative effects on both serum-ind uced proliferation of serum-starved quiescent VSMCs and actively proliferat ing non-confluent VSMCs. Treatment of serum-starved quiescent VSMCs with 1- 8 mmol/l concentration of butyrate caused a concentration-dependent decreas e in serum-induced VSMC proliferation and cell proliferation-associated inc rease in total cellular proteins and RNA levels. Similarly, exposure of act ively growing VSMCs to 5 mmol/l butyrate resulted in the inhibition of cell proliferation and proliferation-induced increase in cellular proteins and RNA levels. Furthermore, cellular morphology was significantly altered. Ana lysis of cell cycle regulatory proteins indicated that levels of PCNA, an e xcellent marker for cell proliferation, was significantly altered by butyra te both in actively proliferating and serum-induced quiescent VSMCs. These observations suggest that butyrate exhibits potential antiatherogenic capab ility by inhibiting VSMC proliferation and proliferation-associated increas e in PCNA expression and thus merits further investigations regarding thera peutic significance of butyrate in vascular proliferative disorders.