Hypertension research could yield advancements in CVD prevention
Hypertension is one of the most common risk factors for CVD, and despite numerous therapies existing, rates of uncontrolled hypertension have risen since the start of the COVID-19 pandemic.
Understanding and controlling hypertension is a key toward prevention of cardiovascular disease and is a major component of the mission of the Cardiovascular Translational Research Center at the University of South Carolina, which was launched in 2020 to promote integrated research into the pathogenesis, diagnosis and treatment of cardiovascular disease in South Carolina and throughout the U.S.
R. Clinton Webb, PhD, director of the Cardiovascular Translational Research Center and recipient of the 2018 Excellence Award for Hypertension Research from the American Heart Association’s Council on Hypertension, has led research on a number of hypertension-related topics, including the role of cell damage in hypertension and the relationship between changes in the vasculature and hypertension. He spoke with Healio about key topics in hypertension research and the goals of the Cardiovascular Translational Research Center.
Healio: What are some of the most active areas in hypertension research currently?
Webb: The most active areas in terms of treatment are around angiotensin II and the renin-angiotensin system, because that’s where we treat most hypertension.
In terms of activity that we are trying to get a better understanding of, inflammatory responses as they relate to the innate and adaptive immune responses are an area of interest. Our team studies innate immunity more than adaptive, but there is a lot of interest in adaptive immunity.
Healio: What is the role of vascular reactivity in hypertension?
Webb: Hypertension is inherited, at least partially. But there are secondary forms of hypertension, and a whole step of pathways that can be changed by having poor genetics or having a secondary form of hypertension. Those pathways include immunity and inflammatory responses. But the final common pathway that causes BP elevation has to be something that changes in the vasculature. Very few forms of hypertension are maintained by an increased cardiac output. It is mainly change in the vasculature. So, the blood vessels can either constrict or vasodilate less and cause a BP elevation, or elevation can be caused by remodeling, ie, developing a thicker wall that can encroach upon the lumen of the blood vessel, which gives a mechanical advantage to keep BP elevated. Increased vasoconstriction, reduced vasodilation and enhanced wall thickness that encroaches upon the lumen are the three vascular changes seen in hypertension.
Healio: What is the cellular impact of hypertension?
Webb: This is a complicated issue, and I have run into roadblocks trying to get funding to research it. Here is one way to consider it. The linemen on a football team all get hypertension during the season, which goes away when the season ends, but the players at the other positions do not. Part of the problem is that when a player collides with another one, they are going about 35 miles per hour, which causes an injury to the body. The bruises they get are actually broken-up cells. And when cells break up, elements of them get outside the cell that should not be. One is mitochondria, which evolved from bacteria that entered the cell. When cells break apart and the mitochondria get outside, they look like bacteria. And they are very inflammatory. The mitochondrial DNA and double-stranded RNA set off a cascade of inflammatory responses. This is an example of how cell injury plays a role in inflammation and hypertension.
We have millions of cells that die every day. In hypertensive individuals, there seems to be an increase in necrotic injury. It could be hydraulic because the BP itself has increased, killing cells. But for whatever reason, people with hypertension have an increase in cell damage.
Healio: What have we learned recently about the interaction between blood pressure and inflammation?
Webb: There is no doubt that there is a circular event in play. As BP goes up, you get more and more injury. The more injury that occurs, the more material comes out of the cells, and the more inflammatory the condition becomes.
There are also other things that feed into it. The football players I mentioned also have metabolic syndrome, which means they may not be prediabetic but are heading toward that. This is partly due to their diet and to their activities on the field. Being overweight causes a metabolic load on the system, which causes an increase in inflammatory condition, which impacts hypertension. So diabetes and other metabolic disorders often go hand in hand with hypertension because of how these systems interact.
Healio: What is the goal of the Cardiovascular Translational Research Center?
Webb: The goal is to address CV and health conditions in South Carolina and beyond. Approximately half of the population in South Carolina has hypertension, and the same is true for many other states. The initiative is to bring scientists together along with prominent leaders, hospitals, doctors and companies to address problems with CVD, a major issue in South Carolina and across the nation.
Healio: What does the team at the Cardiovascular Translational Research Center hope to investigate in the future?
Webb: One area of interest is cytomegalovirus, a virus that approximately 90% of people have from birth. Most individuals are asymptomatic, and the virus is not a problem for them. But in some people, the cytomegalovirus becomes reactivated. When that happens, it hijacks G protein-coupled receptors, which are special receptors on the cell of the membrane, in order to maintain its infectious state. The problem is, the G protein-coupled receptors are on endothelial cells and smooth muscle cells, and they play a role in constrictor responses and dilator responses. So chemokines, which are involved with hypertension, bind to these receptors and cause constriction. And that is very interesting to us right now.
We are also interested in cell-free DNA and how it causes CVD. Camilla Ferreira Wenceslau, PhD, MS, FAHA, is interested in sepsis and metabolic syndrome. Cameron McCarthy, PhD, has an interest in autophagy, energy sensing and ketogenic interventions as related to CVD.
Another area we are very interested in is inflammasome activation and hypertension. We are especially interested in chronic unpredictable stress, which is common in people in war areas, as well as in African American individuals, but is experienced by all of us at some point or another. When we change something about a mouse’s environment every day for 28 days, at the end of those 28 days, they have hypertension, particularly the males. We are interested in what happens in the heart, the brain, the kidney and the vasculature as a result of this. Chronic stress causes hyperactivation of the sympathetic nervous system, and having an increase in sympathetic drive changes how the blood vessels, kidney and heart react. The inflammasomes we are interested in are the NLRP3 and ANG2.
Healio: Is there anything else you would like to mention?
Webb: The center is not just an initiative for the School of Medicine, but is campus-wide. We have members in biomedical engineering, biology, psychology and other disciplines.
For more information:
R. Clinton Webb, PhD, can be reached at clinton.webb@uscmed.sc.edu.
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