Gene activity changes in fatty tissue linked to high blood pressure

1,000-plus genes found to have differing activity levels in Cushing’s patients

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Alterations in the activity of a signaling system called RAAS in fatty tissue could contribute to high blood pressure in people with Cushing’s syndrome, according to a recent report.

Data showed gene activity associated with renin-angiotensin-aldosterone-system (RAAS) was altered in fatty tissue from Cushing’s patients relative to people without the disease, particularly in those with the highest blood pressure.

Tissue from Cushing’s patients also showed alterations in gene activity related to fatty cell (adipocyte) health and immune function.

Altogether, the analyses indicate, “a wide range of physiological consequences on the adipose tissue during [Cushing’s syndrome], with major cell populations and important pathways and genes being affected,” the researchers wrote.

The study, “Unique Gene Expression Signature in Periadrenal Adipose Tissue Identifies a High Blood Pressure Group in Patients With Cushing Syndrome,” was published in the journal Hypertension.

In all forms of Cushing’s syndrome, including Cushing’s disease, excessive release of the hormone cortisol from the adrenal glands drives symptoms including obesity, high blood pressure, diabetes, and cardiovascular disease, among others.

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Abnormal accumulation of visceral adipose tissue

Obesity in Cushing’s is associated with the abnormal accumulation of visceral adipose tissue, or the fat that lines internal organs. This tissue is metabolically and hormonally active, and can significantly influence biological processes.

Researchers believe that changes in this adipose tissue in Cushing’s patients could contribute to the high blood pressure, or hypertension, that’s commonly observed in the disease. While hypertension is a significant contributor to cardiovascular dysfunction in Cushing’s, the mechanisms underlying it are not fully worked out.

In their study, researchers explored this possibility by examining the gene expression (activity) profile of adipose tissue found near the adrenal glands in Cushing’s patients who underwent adrenal surgery at a hospital in Germany.

Tissue samples were obtained from 12 people with Cushing’s syndrome due to cortisol-producing tumors in the adrenal glands, and five who had an adrenal tumor not associated with Cushing’s and served as a control group.

Cushing’s patients, all of whom were women, had a mean age of 44.5 years. They also had higher blood pressure than controls.

Overall, more than 1,000 genes were found to have different activity levels in Cushing’s patients compared with controls. These genes were linked to a variety of biological processes.

Among the predicted alterations in Cushing’s tissue was an increased abundance of immune monocytes and altered activity of immune-related genes, as well as reductions in adipocytes — the specialized cells that make up fatty tissue — and lower activity of genes related to adipocyte health and function.

Increase in endothelial cells in active Cushing’s

Endothelial cells, which line blood vessel walls, were increased in active Cushing’s, whereas the smooth muscle cells involved in regulating blood pressure and flow in the cardiovascular system were decreased, altogether “suggesting an effect on the local vascular system.”

Correspondingly, gene expression analyses indicated altered activity of genes associated with RAAS in adipose tissue. RAAS is a critical regulator of blood pressure and cardiovascular function and has been previously linked to hypertension in Cushing’s.

A particular subgroup of Cushing’s patients were found to have significantly higher blood pressure levels and a pronounced hypertensive profile.

Relative to Cushing’s patients with lower blood pressure, these hypertensive patients showed a distinct gene activity profile in adipose tissue, including in genes associated with RAAS. This included a tendency toward higher activity of the REN gene.

REN activity in adipose tissue, but not in the blood, was overall found to be significantly correlated with blood pressure in Cushing’s patients.

REN, or renin, protein levels tended to be increased in adipose tissue, but not in the bloodstream, of Cushing’s patients relative to controls. Blood REN levels were significantly reduced in the subset of Cushing’s patients with higher blood pressure relative to those with lower blood pressure.

Altogether, “we show for the first time a relevant association of the local [RAAS] and systemic blood pressure levels in patients with [Cushing’s syndrome],” the researchers wrote.

“We propose that, induced by local cortisol excess, RAAS activity could influence the hypertensive phenotype [manifestations] in patients with endogenous [Cushing’s syndrome],” they wrote.

Blood pressure was generally reduced in Cushing’s patients six months after surgery, although those in the high pressure subgroup still tended to have higher blood pressure.

That finding suggests, “potential long-lasting effects of adipose tissue RAAS components despite sustained biochemical remission of [Cushing’s syndrome],” the researchers wrote.

This could in part underlie the observation that Cushing’s patients remain at an increased risk of cardiovascular complications “even years after … remission.”