New target for treating salt-induced hypertension

December 17, 2007 By Benjamin A. Olenchock, M.D. Ph.D. [mailto:bolenchock@partners.org]

Heidelberg Systemic blood pressure is determined by vascular tone, which is regulated on a molecular level by the phosphorylation of myosin light chain (MLC). This modification helps myosin interact with its partner actin, causing shortening of the contractile fibers in smooth muscle cells and increased vascular tone. A combination of hormonal, neural and rheological (blood-flow) signals act through receptors on smooth muscle cells to affect MLC phosphorylation. Researchers have conditionally deleted different molecules involved in transducing these signals in order to determine which signals are important for blood pressure control. Their findings, published online in Nature Medicine, demonstrate that a certain subset of G-proteins (the G12 and G13 proteins) are essential for salt-induced hypertension but not basal blood pressure. These results identify a new target for anti-hypertensive medicines.

There are two major signaling networks governing MLC phosphorylation. One involves receptors that signal through Gq and G11 proteins, leading to activation of the enzyme that adds the phosphate group. The other receptors signal through the G12 and G13 proteins, leading to in-activation of the enzyme which removes the phosphate group.

The researchers used an inducible Cre-lox system to specifically delete G-alpha-13 or G-alpha-q specifically in smooth muscle cells. They then crossed these mice to either G11 or G12 deficient backgrounds, making mice that lack the G12-G13 signaling pathway (12-13-KO), and mice that lack the Gq-G11 signaling pathway (q-11-KO) in all of their smooth muscle cells.

After gene deletion, the q-11-KO mice had a drop in mean arterial pressure, whereas the 12-13-KO mice maintained normal blood pressure. Blood pressure elevation in response to pressors (angiotensin II, vasopressin, phenylephrine and endothelin-1) were blunted in the q-11-KO mice. The 12-13-KO mice had slightly blunted responses to vasopressin, endothelin-1 and U46619.

To investigate the impact of these receptors on salt-induced hypertension, mice had one kidney removed and were implanted with deoxycorticosterone acetate pellet and given salt in their drinking water. Prior to gene deletion, both the q-11-KO mice and the 12-13-KO mice had elevated blood pressures on the high salt diet. Following gene deletion, however, the blood pressure returned to normal in both the q-11-KO and the 12-13-KO mice, despite continued high salt diet.

This paper used an in vivo genetic deletion model to delineate two signaling pathways in vascular smooth muscle: one that signals through Gq and G11 to phosphorylate MLC, and one that acts through G12 and G13 to inhibit de-phosphorylation of MLC. Their main result is interesting: the Gq/G11 signaling pathway is important for both basal vascular tone and salt-induced hypertension, whereas the G12/G13 signaling pathway is dispensable for basal vascular tone but is essential for salt-induced hypertension. This finding might lead to new therapeutics targeting the G12/G13 signaling pathway specifically.

Angela Wirth, Zoltán Benyó, Martina Lukasova, Barbara Leutgeb, Nina Wettschureck, Stefan Gorbey, Petra Örsy, Béla Horváth, Christiane Maser-Gluth, Erich Greiner, Björn Lemmer, Günther Schütz, Silvio Gutkind & Stefan Offermanns. G12-G13–LARG–mediated signaling in vascular smooth muscle is required for salt-induced hypertension. Nat Med Published online: 16 December 2007; | doi:10.1038/nm1666