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The link between dying cells and hypertension
02-21-2017
by Jeffrey Bouley  |  Email the author
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AUGUSTA, Ga.—As Augusta University notes, “It’s been known for decades that a bacterial infection can raise your blood pressure short term, but now scientists are putting together the pieces of how our own dying cells can fuel chronically high, destructive pressure.” A recent grant is expected to help this work along.
 
As the university explains, billions of cells in our bodies die each day and “their remains are mostly taken up by garbage-eating immune cells like macrophages.” But, apparently, scientists have increasing evidence that when this massive cell die-off increases because of high blood pressure, the cellular debris that piles up in turn attracts the attention of the immune system. This leads to inflammation and blood vessel constriction that helps to worsen the hypertension.
 
“It’s a circle,” said Dr. R. Clinton Webb, chairman of the Department of Physiology at the Medical College of Georgia at Augusta University—one in which he notes that inflammation is a constant and which isn’t addressed in today’s treatment regimens.
 
“The more blood pressure goes up, the more injury you have,” said Webb, and he and his colleagues want to understand the signaling pathways that are driving this inflammation that further drives blood pressure.
 
Making that understanding more accessible is a $9.4-million program project grant from the National Heart, Lung and Blood Institute aimed at further parsing how contents regularly spilt from a surplus of dying cells contribute to this vicious circle of hypertension. Webb, a vascular expert, is principal investigator for the project.
 
What is known right now about this presumed unhealthy synergy between hypertension and cell death is that higher blood pressure—from causes like obesity to genetics to salt sensitivity—increases cell death. Once outside the dying cell, typical contents like DNA as well as HMGB1, which helps stabilize the DNA, are categorized as damage associated molecular patterns, or DAMPs.
 
As August University notes, DAMPs are considered “alarm signals” because they look like bacterial or viral invaders to the immune system. That sets in motion likely well-intended inflammation to fight the invader but blood-vessel constriction and narrowing, kidney and other organ damage, and more cell death also follows.
 
The new grant, the university reports, is enabling Webb and his team to look at what happens when the increased cell carnage inside blood vessel walls increases the release of DNA from mitochondria—DNA which actually is distinctly different from our own.
 
Project leaders Drs. Jennifer Sullivan and Paul O’Connor, respectively, are exploring how the different ways cells die in male and female bodies impact the damage that follows the release of HMGB1, and how an onslaught of these and other DAMPs cripple the kidney’s ability to help regulate blood pressure.
 
Dr. Adviye Ergul, a vascular physiologist, is managing the bioinflammation core, and Dr. Michael Brands, a cardiovascular-renal physiologist, is managing the animal use and instrumentation core for the five-year studies to ensure the consistency of results gathered and minimal animal usage.
 
Webb thinks DAMPs are both the result of and initiators of hypertension in many people who suffer from the condition.
 
“Cells are dying all over if you have hypertension,” Sullivan elaborated. Smooth muscle cells and endothelial cells that comprise the blood vessels are definite casualties, and Webbs adds: “There is no doubt there are more dead cells in the hypertensive blood vessel.”
 
Like bacteria, DAMPs activate Toll-like receptors (TLRs) that can be found inside many cells and outside others, although they are known to translocate. The nine different types of TLRs also have in common some degree of activation of MYD88, a downstream molecule, which in turn activates transcription factor NF-kB, which helps control gene expression as well as cell death and growth. In the case of activation by DAMPs, TLRs initiate inflammation, a good reaction when, for example, TLR4 responds as it should to a membrane component of bacteria.
 
But Webb’s team is focusing on what happens inside blood vessels when excessive cell death leads to excessive release of the mitochondrial DNA. Even with its foreign DNA, as with other DAMPs, all is fine until mitochondrial DNA gets spilled. At that moment it can start to activate TLR9s inside immune, vascular smooth muscle or endothelial cells, Webb said. One of the many questions the researchers want to answer is whether TLR4 and TLR9 have some unfortunate inflammatory synergy through their activation of MYD88 in this scenario.
 
The long-term goal of Webb and his colleagues is to identify targets that could block some of the unintended results without putting people at risk for additional disease by generally suppressing their natural immune response.
 
“Imagine, for example, if you could figure out a drug that would actually block say the uptake of mitochondrial DNA,” Webb said.
 
Or, as Sullivan notes, perhaps a drug that reduces excessive activation of T cells, the drivers of the immune response.
 
“There is this growing interest in the adaptive immune response and T cells being important in causing increases in hypertension,” Sullivan said of a finding that has been shown in animal models and people. “There is evidence of T cell activation, but what is causing it?” Knowing that answer could lead to treatment that selectively blocks excess activation, so the scientists are looking upstream for activators.
 
And going back to the first part of this article and the fact that this relationship between cell death and hypertension is well-known—if not well understood—here is the abstract from a 1995 paper, titled “Apoptosis in target organs of hypertension,” published in the journal Hypertension: “Apoptosis or programmed cell death frequently parallels abnormalities in cell proliferation and differentiation. As hypertrophy/hyperplasia or remodeling occurs in organs affected by hypertension, we evaluated the degree of apoptosis in the heart, kidney, and brain in situ in genetically hypertensive mice and rats as well as in cultured vascular smooth muscle cells. Apoptosis was characterized by morphological features, DNA fragmentation, and laddering as well as by terminal deoxynucleotidyl transferase labeling of the 3' OH ends of both extracted DNA and tissue sections. The present report provides the first evidence of increased apoptosis in whole organs of genetically hypertensive rat and mouse strains: in the heart of spontaneously hypertensive rats (SHR) and in the heart (ventricular cardiomyocytes), kidney (inner cortex and medulla), and brain (cortex, striatum, hippocampus, and thalamus) of spontaneously hypertensive mice, with a higher effect of apoptotic inducers in cultured aortic smooth muscle cells derived from SHR. Both types of known apoptotic processes, oligonucleosomal cleavage and large DNA fragmentation, were observed in vascular smooth muscle cells, but only the former appeared to be increased in SHR. This study underlines the importance of cell death dysregulation in hypertension, reveals a new route for investigation of the pathogenesis of hypertension, and suggests novel targets of therapeutic intervention.”
 
Perhaps the researchers at Augusta University can help move the needle from “suggestions” of therapeutic interventions dealing with this problem to actual ones.
 
SOURCE: Augusta University
 
Code: E02221702

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