Insulin-like growth-factor-1-induced PKB signaling and Egr-1 expression is inhibited by curcumin in A-10 vascular smooth muscle cells.

Insulin-like growth factor 1 (IGF-1) is a mitogenic factor that stimulates the signaling pathways responsible for inducing hypertrophic and proliferative responses in vascular smooth muscle cells (VSMC). We have previously demonstrated that IGF-1 receptor (IGF-1R) plays a key role in transducing the hypertrophic and proliferative responses of angiotensin II (Ang-II) and endothelin-1 (ET-1). Curcumin, a polyphenolic compound derived from the spice turmeric is known to possess antiproliferative properties and exerts vasculoprotective effects. However, the ability of curcumin to modulate IGF-1-induced signaling responses in VSMC remains to be investigated. In this study, we determined the effect of curcumin on IGF-1-induced phosphorylation of protein kinase B (PKB), glycogen synthase kinase-3ß (GSK-3ß), and IGF-1R in VSMC. Curcumin inhibited IGF-1-induced phosphorylation of PKB and GSK-3ß as well as the IGF-1R ß subunit in a dose-dependent fashion. In addition, IGF-1-induced expression of early growth response protein 1 (Egr-1) which plays a pathogenic role in vascular dysfunctions, was also attenuated by curcumin. In conclusion, these results indicate that curcumin is a potent inhibitor of key components of the IGF-1-induced mitogenic and proliferative signaling system in VSMC, and suggest that curcumin-induced attenuation of these signaling components may constitute a potential mechanism for its vasculoprotective effects.

Attenuation of endothelin-1-induced PKB and ERK1/2 signaling, as well as Egr-1 expression, by curcumin in A-10 vascular smooth muscle cells.

Endothelin-1 (ET-1) is implicated in the pathogenesis of vascular abnormalities through the hyperactivation of growth promoting pathways, including protein kinase B (PKB) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. ET-1 has been shown to elicit its responses through the generation of reactive oxygen species (ROS). Curcumin, the main constituent of the spice turmeric, exhibits cardio-protective, anti-proliferative, and antioxidant properties; however, the precise molecular mechanism of its action is unclear. Therefore, in the present study, we investigated the effects of curcumin on ET-1-induced PKB and ERK1/2 signaling, as well as insulin-like growth factor type receptor (IGF-1R) phosphorylation. Curcumin dose-dependently inhibited ET-1-induced phosphorylation of PKB, ERK1/2, c-Raf, and insulin-like growth factor type 1 receptor (IGF-1R), in vascular smooth muscle cells (VSMC). Furthermore, curcumin also attenuated ET-1-induced expression of early growth response (Egr)-1, a transcription factor downstream of ERK1/2 that plays a regulatory role in several cardiovascular pathological processes. In conclusion, these data demonstrate that curcumin is a potent inhibitor of ET-1-induced mitogenic and proliferative signaling events in VSMC and suggest that the ability of curcumin to attenuate these events may contribute as a potential mechanism for its cardiovascular protective response.

Cardiovascular protection by curcumin: molecular aspects.

Curcumin is the active component in turmeric--a spice that has been extensively used as a culinary agent and a home remedy to prevent and treat many diseases in India and other countries for hundreds of years. However, systematic studies to understand the molecular basis of disease preventing or therapeutic properties of curcumin began to appear in the scientific literature only during the last 40 years. As a result of these studies, substantial evidence has accumulated to suggest that curcumin can affect signaling pathways linked to cellular growth, proliferation, survival, inflammation and transcription. In addition, curcumin has also been shown to exert anti-atherosclerotic, anti-cancer, anti-diabetic, anti-inflammatory and anti-oxidative properties in animal models of various diseases and in human subjects. In this article, we highlight the cardiovascular protective role of curcumin with an emphasis on the molecular basis of this effect.

Modulatory Role of Nitric Oxide/cGMP System in Endothelin-1-Induced Signaling Responses in Vascular Smooth Muscle Cells.

Nitric oxide (NO) is an important vasoprotective molecule that serves not only as a vasodilator but also exerts antihypertrophic and antiproliferative effects in vascular smooth muscle cells (VSMC). The precise mechanism by which the antihypertrophic and antiproliferative responses of NO are mediated remains obscure. However, recent studies have suggested that one of the mechanisms by which this may be achieved includes the attenuation of signal transduction pathways responsible for inducing the hypertrophic and proliferative program in VSMC. Endothelin-1 is a powerful vasoconstrictor peptide with mitogenic and growth stimulatory properties and exerts its effects by activating multiple signaling pathways which include ERK 1/2, PKB and Rho-ROCK. Both cGMP-dependent and independent events have been reported to mediate the effect of NO on these pathways leading to its vasoprotective response. This review briefly summarizes some key studies on the modulatory effect of NO on these signaling pathways and discusses the possible role of cGMP system in this process.