A signaling pathway implicated in the development of cancer also contributes to salt sensitivity of blood pressure (SSBP), an independent risk factor for cardiovascular disease and death, according to researchers at Vanderbilt University Medical Center.
About half of all people with high blood pressure exhibit SSBP. Their blood pressure goes up or down acutely, mirroring high or low consumption and resulting blood levels of dietary salt (primarily sodium chloride). But salt sensitivity also occurs in about 25% of people who do not have hypertension.
Despite the well-established link between high salt intake and cardiovascular disease and stroke, “the mechanism of SSBP is poorly understood, and it remains an untreatable cardiovascular risk with no widely available diagnostic tool,” the VUMC researchers reported recently in the journal Circulation Research.
The paper’s corresponding author, Annet Kirabo, DVM, MSc, PhD, has been studying this phenomenon for years. An associate professor of Medicine in the Division of Clinical Pharmacology, she and her colleagues have found clues in the immune system.
They have reported previously that elevated sodium activates antigen-presenting myeloid cells, part of the body’s immune repertoire. A concomitant rise in blood pressure may be related to an increased production of pro-inflammatory signaling molecules (cytokines) and highly reactive compounds called isolevuglandins.
In the current study, the researchers investigated the JAK/STAT/SMAD signaling pathway, which is important in cell development and immune responses, as well as cancer and cardiovascular disease.
In patients with salt-sensitive hypertension, rapid salt loading and depletion — increased or decreased salt consumption — triggered corresponding changes not only in blood pressure but in the expression of certain genes in this pathway in antigen-presenting cells (APCs).
Expression of three components of the pathway, the enzyme JAK2, and proteins STAT3 and SMAD3, rose after salt loading and declined after salt depletion in salt-sensitive patients. These changes in gene expression did not occur in the APCs of patients with salt-resistant hypertension.
To confirm JAK2’s role in SSBP, the researchers studied the effect of deleting the JAK gene from an APC called CD11c+. “Knocking out” the gene in a mouse model blocked downstream activation of STAT3 and SMAD3, reduced secretion of cytokines and isolevuglandins, and prevented salt-induced hypertension.
These findings suggest that JAK2 activation of downstream signaling in APCs may be a biomarker for diagnosing SSBP and a potential target for treating salt sensitivity, the researchers concluded.
“Our study on myeloid JAK2 and salt-sensitive hypertension (also) opens new doors for understanding cardiovascular complications in cancer patients,” Kirabo noted. “Given JAK2’s well-established role in cancer, this research highlights the intersection of hypertension and oncology, emphasizing the need for cardio-oncology strategies that address salt sensitivity in patients undergoing cancer treatment.”
Mohammad Saleem, PhD, a research instructor in Medicine in the Kirabo lab, is the paper’s first author.
Other VUMC co-authors are Luul Aden, Ashley Pitzer Mutchler, PhD, Chitra Basu, PhD, Lale A. Ertuglu, MD, Quanhu Sheng, PhD, Niki Penner, Anna Hemnes, MD, Jennifer Park, Jeanne A. Ishimwe, PhD, Cheryl Laffer, MD, PhD, the late Fernando Elijovich, MD, Celestine Wanjalla, MD, PhD, Néstor de la Visitación Pastor, PhD, Paul Kastner, Claude Albritton, Taseer Ahmad, PharmD, MPhil, PhD, Alexandria Haynes, Justin Yu, Meghan Graber, Sharia Yasmin, Antonis Hatzopoulos, PhD, Eric Gamazon, PhD, MS, and Alexander Bick, MD, PhD.
The research was supported in part by National Institutes of Health grants R01HL147818, T32HL144446, R03HL155041, R01HL144941 and K23HL156759; the Doris Duke Charitable Foundation; the Burroughs Wellcome Fund; and the American Heart Association.
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