Furthermore, taking away the ability of fast, steady flow to phosphorylate HDAC5 greatly weakened a second lifesaving benefit of flow: it prevents white blood cells from sticking to the cells lining blood vessels, an early, necessary step in the development of atherosclerosis. Fatty diets cause cholesterol deposits to build up within arterial walls, deposits that white blood cells "see" as infections and home in on to drive inflammatory disease. By increasing KLF2 expression, blood flow force is believed to prevent adhesion molecules on cells lining arteries from snagging white blood cells as they float by.
The team also showed through a series of experiments that flow-induced HDAC5 phosphorylation depends on the well known calcium/calmodulin pathway. The team theorizes that the force of flow changes the shape of calcium channels on the surface of endothelial cells, which enables calcium to rush into the cells and turn on calmodulin, which attaches to an as yet unidentified kinase that phosphorylates HDAC5.
Identifying such an enzyme would complete the first diagram of a flow-sensitive, protective signaling pathway. Jin's lab has zeroed in on calmodulin-dependent kinases as likely suspects, and is designing experiments that will shut down the genes coding for them to see if that stops the phosphorylation of HDAC5 by flow. Should that be the case, the team will seek to screen for drug candidates that encourage the action of these enzymes.
Along with Jin and Wang, the effort was led at the Aab CVRI by Chang Hoon Ha, Bong Sook Jhun and Chelsea Wong. Mukesh Jain led a partnering effort at the Case Western Reserve University School of Medicine. Much of the early work in area was done in the labs of Bradford Berk, M.D., Ph.D., CEO of the University of Rochester Medical Center, and Jun-ichi Abe, M.D., Ph.D., associate professor within the Aab CVRI. Funding for the work of Jin's team came from the American Heart Association, the American Diabetes Association and the National Heart, Lung and Blood Institute (NHLBI), part of the National Institutes of Health. The article was published online on Dec. 30, 2009.
"If we could free MEF2 from HDAC5 with a drug, we could mimic flow force to enhance KLF2 and eNOS expression and reverse inflammation in vessel walls," Jin said. "That promises to be extremely useful, and potentially to stave off disease underway in the blood vessels of humans."
Source: University of Rochester Medical Center