Researchers at Vanderbilt University Medical Center have developed a new computational and experimental approach to discover peptide antigens that cause hypertension by activating T cells.
Their findings, reported recently in the Journal of Clinical Investigation, could lead to new, more effective treatments for hypertension, a leading cause of death in the United States.
The first-ever isolation of specific hypertension-promoting peptides results from several lines of converging evidence, noted the paper’s corresponding author, David G. Harrison, MD, the Betty and Jack Bailey Professor of Cardiology and director of the Division of Clinical Pharmacology at VUMC.
One of the distinguishing characteristics of hypertension is the accumulation in the kidneys of cytotoxic immune cells, called CD8+ T cells, which normally seek out and destroy other cells in the body that have become infected by bacteria or viruses, or which are malignant (cancerous).
In the case of inflammatory diseases like hypertension, however, proliferating CD8+ T cells attack normal tissues and injure the “end organs” of chronic disease, notably the heart, blood vessels and kidneys.
Also associated with hypertension and related diseases is a buildup of isolevuglandins (IsoLGs), highly reactive compounds that bind to and modify peptides and large polypeptides (proteins) in harmful ways.
Another player is the dendritic cell, which processes and presents peptide markers from cell surfaces in what are called “major histocompatibility complexes” (MHCs). These “self-antigens” normally enable T cells to distinguish “self” (normal cells) from “nonself” (infected or cancerous cells), and thus avoid attacking healthy tissue.
In animal models of hypertension, however, T cells proliferate when exposed to dendritic cells presenting IsoLG-adducted (modified) peptides. In the current study, the researchers discovered that these antigens are uniquely presented only by one subset of MHCs and used this information to determine the required structure of IsoLG-modified peptides.
Like detectives deducing suspects from the scene of a crime, they used computational methods to identify, screen and study potential peptides with this structure that could be produced in mice and humans.
When modified by IsoLGs, four of the candidate peptides activated CD8+ T cells and promoted hypertension in mice. Using probes made from these peptides, the researchers were able to find activated T cells in the aorta, kidneys and bone marrow, but only in hypertensive mice.
The findings “strongly suggest that (these) peptides … play a role in the genesis of hypertension and its related end-organ damage,” they concluded.
“Understanding the specific peptides that are IsoLG-adducted in hypertension would be extremely informative,” they wrote, “providing insight into the cells and subcellular locations where this pathologic process occurs and … (potentially) therapeutic opportunity to intervene and arrest it.”
For example, in animal models of hypertension, 2-hydroxybenzylamine (2-HOBA), a naturally occurring antioxidant that can “scavenge,” or mop up IsoLGs, inhibits adduct formation and limits end-organ damage caused by high blood pressure.
The paper’s first author, Nathaniel Bloodworth, MD, PhD, a former postdoctoral fellow in Clinical Pharmacology at VUMC, is now associate medical director of the Physician Development Program at AbbVie Pharmaceuticals.
Other co-authors from VUMC and Vanderbilt University are:
- Wei Chen, MD, PhD, Kuniko Hunter, and David Patrick, MD, PhD, Department of Medicine, Division of Clinical Pharmacology
- Sean Davies, PhD, Department of Pharmacology, and Mingfang Ao, PhD, Department of Anesthesiology
- Amy Palubinsky, PhD, Elizabeth Phillips, MD, and Simon Mallal, MBBS, Department of Medicine, Division of Infectious Diseases
- Rocco Moretti, PhD, and Jens Meiler, PhD, Department of Chemistry, Center for Structural Biology
This work was supported in part by National Institutes of Health grants R35HL140016, T32HL144446, K08HL153789, R01HG010863, P30CA033572, P30CA068485, P01HL116263, and R01DA046138.