Our Research

Endothelial cells stained with fluorescent phalloidin.

Our laboratory takes a multi-disciplinary, translational approach to vascular biology. We are interested in factors and signaling molecules which regulate the vascular wall during atherogenesis and vascular inflammation. Our laboratory has studied the role of heterotrimeric G-proteins in mediating NO release in vascular endothelial cells and showed that atherogenic lipoproteins, especially LDL, inhibit NO release via differential modulation of G-protein function and expression. Our laboratory also found that NO decreases the expression of these adhesion molecules through the inhibition of the pro-inflammatory transcription factor, NF-kappaB. These findings provide a therapeutic target for NO’s anti-inflammatory effects.

ROCK1 and ROCK2 and its method of activation.

Another important biological function of NO is the regulation of vascular tone and blood flow. An important observation made in our laboratory which may have clinical benefits is the discovery that a class of cholesterol-lowering agents, HMG-CoA reductase inhibitors or statins, upregulate the expression and activity of eNOS and protect against ischemic strokes. 1 Many of these effects depend on the ability of statins to block the synthesis of the isoprenoid intermediates such as farnesylpyrophosphate or geranylgeranylpyrophosphate, which are important lipid attachments for intracellular signaling molecules. Indeed, our laboratory has demonstrated that statins inhibit the isoprenylation of small GTP-binding proteins belonging to the Rho GTPase family, and the inhibition of Rho geranylgeranylation, and its downstream effector Rho-kinase, may play an important role in mediating some of the so-called “pleiotropic” effects of statins. 2

Ischemic cascade in the blood brain barrier.

Furthermore, our laboratory is interested in the pathophysiology and mechanism of ischemic stroke. Our laboratory has demonstrated that the Rho/ROCK signaling pathway is vital for the activation of platelets for hemostasis, where ROCK2-deficient platelets led to prolonged bleeding and increased time to vascular occlusion following vascular injury. These findings indicate that platelet ROCK2 is critical for thrombus formation and stabilization, and is an important pathogenic mediator of thromboembolic stroke. 3

  1. Laufs U, La Fata V, Plutzky J and Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation. 1998;97:1129-35. ↩
  2. Laufs U and Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem. 1998;273:24266-71. ↩
  3. Sladojevic N, Oh GT, Kim HH, et al. Decreased Thromboembolic Stroke but not Atherosclerosis or Vascular Remodeling in Mice with ROCK2-deficient Platelets. Cardiovascular Research. 2017 Apr 14. ↩