Homocysteine regulates endothelin type B receptors in vascular smooth muscle cells

• Vascular smooth muscle endothelin type B (ETB) receptor is involved in the pathogenesis of cardiovascular diseases (CVDs). Hyperhomocysteinemia is an independent risk factor for CVDs. The present study was designed to examine the hypothesis that homocysteine (Hcy) up-regulates vascular smooth muscle ETB receptors. In vitro experiments were performed in rat superior mesenteric artery (SMA) and vascular smooth muscle cells (VSMCs). The rat SMA or VSMCs were cultured in serum-free medium for 24 h in the presence and absence of Hcy with or without specific inhibitors for the ERK1/2 signaling pathway and NF-κB. In vivo, the rats received subcutaneous injections of Hcy in the presence or absence of specific inhibitors for the ERK1/2 signaling pathway (U0126) for 3 weeks. Levels of protein expression were determined using Western blot analysis. The contractile responses to sarafotoxin 6c (an ETB receptor agonist) were studied using a sensitive myograph. The blood pressure of the rats was measured via a noninvasive tail-cuff plethysmography method. The results from in vitro experiments showed that Hcy concentration-dependently increased the ETB receptor-mediated contractile responses, and up-regulated ETB receptor expression, in rat SMA. Blockage of the ERK1/2 signaling pathway and NF-κB using the MEK1/2 inhibitor (PD98059 and U0126) or IκB kinase inhibitor (wedelolactone) significantly abolished Hcy-induced up-regulation of ETB receptor. Finally, we used VSMCs as a cellular model to further validate our finding. In vivo study found that hyperhomocysteinemia up-regulated ETB receptor expression, and elevated the blood pressure of rats via the ERK1/2 signaling pathway. In conclusion, Hcy up-regulated vascular smooth muscle ETB receptor via activation of the ERK1/2 signaling pathway and NF-κB.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Kardiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)

Nyckelord

Endothelin type B receptor

ERK1/2

Homocysteine

Hyperhomocysteinemia

NF-κB

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