Steve Lim, Ph.D.
Diseases linked to atherosclerosis are the leading cause of death in the United States. This narrowing of the insides of arteries that impedes blood flow is present in about half of Americans ages 45 to 84, and most do not realize they have atherosclerosis.
To better understand how the disease develops and how it can be controlled is the goal of a new National Institutes of Health grant awarded to Steve Lim, Ph.D., an associate professor in the University of Alabama at Birmingham Department of Pathology Division of Molecular and Cellular Pathology. Lim and colleagues have preliminary evidence that a protein kinase called FAK may promote key changes in vascular smooth muscle cells, or VSMCs. These cellular changes contribute to atherosclerotic lesions, but direct interventional studies that target this process have been lacking, Lim says.
The VSMCs contribute to atherosclerosis through dedifferentiation into a proliferative state after vessel injury, or through a transdifferentiation into macrophage-like cells during atherosclerosis progression. Just as real estate depends on location, location, location, the function of FAK inside the VSMCs that are part of the arterial wall is altered by FAK’s cellular location. In healthy arteries, Lim has found that FAK is inactive and is located primarily in the nuclei of VSMCs. In contrast, after vessel injury, FAK relocates to the VSMC cytoplasm and is active as a kinase, with a corresponding increase in cell proliferation.
Active FAK in VSMCs of mice — after injury of the artery or in mice that are genetically susceptible to atherosclerosis — causes an unwanted proliferation of the VSMCs that helps narrow the artery, suggesting that active cytoplasmic FAK exacerbates atherosclerosis. This notion is further supported by Lim’s observation that FAK shows increased cytoplasmic localization and activity in human atherosclerotic lesions, as compared to healthy human artery specimens. Importantly, mice with a genetic susceptibility to the disease had reduced formation of advanced atherosclerotic lesions when treated with a FAK inhibitor.
Diseases linked to atherosclerosis:
Complications of atherosclerosis may occur suddenly with no warning signs. Some conditions, such as heart attack and stroke, may lead to disability or death. Life-threatening complications include:
• Brain conditions, including a transient ischemic attack or stroke, and vascular dementia that causes cognitive decline beyond the normal aging process.
• Heart problems from coronary heart disease, leading to aortic aneurysms, arrhythmias (irregular heartbeats), cardiac arrest, heart failure or a heart attack.
• Organ damage, including chronic kidney disease that may require dialysis or a kidney transplant, or a narrowing of arteries that supply blood to the intestines, resulting in dead intestinal tissue or serious infections.
• Problems in arms and legs from peripheral artery disease and long-term poor blood flow, which can lead to sores, infections and death of tissue (gangrene).
Source: National Heart, Lung, and Blood Institute
Thus, Lim wants to understand how the presence of FAK in the nucleus — where it is inactive as a kinase — limits VSMC dedifferentiation or transdifferentiation, and instead keeps the VSMCs differentiated as normal contractile cells that divide very slowly. His UAB research team knows that FAK in the nucleus interacts with two proteins that are part of the machineries to alter DNA methylation or remodel nucleosomes — two mechanisms that alter gene expression in the nucleus. Those machineries are known as epigenetic regulators, and nucleosomes are the structural units that tightly package DNA in the nucleus.
So, the hypothesis for Lim’s $1.9 million, four-year grant is this: Inhibition of FAK kinase activity forces FAK to locate into the nucleus, where it promotes maintenance of healthy VSMCs by reducing expression of the two epigenetic regulators that FAK interacts with, the DNMT3A methyltransferase and the NuRD deacetylase complex.
Lim and colleagues will study the molecular mechanisms involved and what happens after vascular injury. They also will assess how FAK inhibition may block VSMC transdifferentiation and promote the stability of plaque blockage in the arteries during early or advanced atherosclerosis.
Support comes from the NIH grant R01HL158800.
Pathology is a department in the Marnix E. Heersink School of Medicine at UAB.