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VU study explores inflammation, hypertension link

Feb. 12, 2015, 8:40 AM

From left, Annet Kirabo, Ph.D., DVM, Mohamed Saleh, Ph.D., Meena Madhur, M.D., Ph.D., David Harrison, M.D., and colleagues are studying how the immune system and inflammation contribute to high blood pressure. (photo by Joe Howell)

The evidence is increasing: the immune system and inflammation are key contributors to high blood pressure.

Now Vanderbilt University researchers have discovered a key role for LNK, an “adaptor” protein that serves as a “brake” to cellular proliferation and cytokine signaling in white blood cells and endothelial cells that make up the inner lining of blood vessels.

Previous genome-wide association studies have identified mutations in the LNK gene in people with hypertension.

In the current study, published this week in the Journal of Clinical Investigation, Meena Madhur, M.D., Ph.D., and colleagues report that deleting or “knocking out” the LNK gene in a mouse model “markedly enhances inflammation, predisposing to hypertension as well as vascular and renal dysfunction.”

Thus, LNK may be a novel target for developing more specific and effective drugs to treat hypertension, the researchers concluded.

Madhur, an assistant professor of Medicine, said that mice deficient in LNK “exhibit increased T cell activation and production of pro-inflammatory cytokines, and this predisposes them to hypertension.”

At a low dose, angiotensin II, a peptide hormone that causes blood vessels to constrict, does not increase blood pressure in normal animals. But in the LNK knock-out animals, the same dose can induce severe hypertension, she said, as well as damaging inflammation in the kidneys.

“The drugs that are used for hypertension right now don’t directly target the immune system,” Madhur said. “We think that’s where the future needs to go.”

“We’re not treating the right thing,” said David Harrison, M.D., the Betty and Jack Bailey Professor of Cardiology, director of the Division of Clinical Pharmacology, and a collaborating investigator in the study.

“We’re trying to get blood pressure down, but there’s all this inflammation going on in the background,” Harrison said. “We’re treating a number (blood pressure) when we need to be thinking about correcting the underlying problem.”

“Interestingly, there are many immunomodulating drugs in use or in clinical trials for autoimmune diseases such as psoriasis and rheumatoid arthritis. We’ve shown in mice that these drugs blunt hypertension,” Madhur said.

“We’re starting to perform clinical trials with some of these drugs,” she said. One trial being conducted by Harrison, Madhur and Cheryl Laffer, M.D., Ph.D., professor of Medicine, is testing the arthritis drug Orencia (abatacept) in patients with resistant hypertension.

Madhur and Harrison’s co-authors included first author and postdoctoral fellow Mohamed Saleh, Ph.D., Annet Kirabo, Ph.D., DVM, research instructor in Medicine, and collaborating investigator Daniel Levy, M.D., of the National Institutes of Health (NIH)

In a related article published in September in the Journal of Clinical Investigation, Kirabo, Saleh, Madhur, Harrison and colleagues reported that dendritic cells, a specialized subset of white blood cells, produce isoketals (an oxidative modification of proteins), which in turn can promote dendritic cell-mediated T cell activation.

The current study was supported by NIH grants HL105294, HL039006, HL58000 and GM015431, an American Heart Association Fellowship to Saleh, and a Vanderbilt Physician Scientist Development Award to Madhur.

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