Adipose (fat) tissue may contribute to the development of pulmonary arterial hypertension (PAH) due to certain metabolic alterations found, for the first time, in patients and also in rodent models of the condition, a study suggests.
The study, “Adipokines and Metabolic Regulators in Human and Experimental Pulmonary Arterial Hypertension,” was published in the International Journal of Molecular Sciences.
PAH is characterized by high blood pressure caused by the narrowing of the pulmonary arteries, blood vessels that transport blood through the lungs.
Recent studies suggest PAH is a systemic disorder in which inflammation and metabolic alterations play a role in its development. Metabolic conditions such as obesity, type 2 diabetes, insulin resistance, and cardiovascular disease have been linked to pulmonary hypertension (PH) and may be implicated in disease onset and severity.
Low-grade chronic inflammation (meta-inflammation) is often triggered by metabolic imbalances and is commonly found in people with metabolic syndrome. This kind of inflammation is thought to be mediated by immune cells in tissues besides the lungs, including the liver, colon, skeletal muscle, and adipose (fat storage) tissue. Still, its impact on PAH is not entirely understood.
Adipose tissue is metabolically active and may be associated with PAH development by producing signaling proteins called adipokines, which regulate several functions, including glucose and fat metabolism, insulin sensitivity, and inflammation.
To investigate further, a team led by researchers based at Brigham and Women’s Hospital in Massachusetts examined various metabolic regulators in blood and lung tissue isolated from PAH patients, and evaluated lung and adipose tissue in three common rodent models of pulmonary hypertension.
“A better understanding of the role of adipokines and meta-inflammation in PAH pathogenesis will provide the basis for therapeutic approaches that may confer benefit in these patients,” the researchers wrote.
Blood samples were collected from 15 PAH patients, mean age of 38.4 years, including four males and 11 females. Also included were 22 age- and gender-matched healthy controls as a comparison group.
Blood test results showed circulating levels of FABP-4 — the primary adipokine produced by adipose tissue involved in fatty acid uptake, transport, and metabolism — were significantly increased in patients with PAH, compared to the control group.
Additionally, adipose-derived adiponectin, implicated in regulating glucose levels as well as fatty acid breakdown, was also significantly increased, as was FGF-21, a signaling protein mainly produced by the liver which stimulates the uptake of glucose in adipose tissue.
Statistically significant positive correlations were found between increased FGF-21 and higher FABP-4 levels, between adiponectin and FABP-4 levels, and between adiponectin and FGF-21.
Analysis of lung tissue isolated from PAH patients found, compared with control tissue samples, increased activity in the genes that encode FABP-4, FGF-21, and related protein PPAR-gamma — a regulator of the formation of adipocytes (fat cells) and insulin responsiveness in adipose tissue.
The team tested three rat models of PAH, including: the MCT model, in which PH is triggered by the chemical MCT; the SuHx rat model, where rats are given Sugen injection and exposed to low oxygen levels (hypoxia) for three weeks; and chronic hypoxia model, in which rats are subjected to hypoxia for two weeks.
The blood pressure in the right heart ventricle was significantly elevated in all three PH-experimental models compared to controls. There was no difference between controls and rat models in the left heart ventricle, which is an indicator of systemic blood pressure.
As seen in human tissues, FABP-4, FGF-21, and PPAR-gamma were significantly upregulated in the lungs in all three PH rat models. While adiponectin was not found in lung tissue, its receptor production was significantly increased in the SuHx model.
PPAR-gamma expression levels were elevated in all three rat models, being significantly increased in the MCT model. Levels of adiponectin and related adiponectin receptors R1 and R2 were significantly increased in the MCT and SuHx models. In the hypoxic model, there was a trend towards elevated adiponectin R1 and R2 but their levels did not reach statistical significance.
Production of Glut-4, a glucose transporter that facilitates insulin-stimulated glucose uptake, was significantly increased in the MCT and SuHx models, and had a non-significant trend in the hypoxic model. Furthermore, production levels of PFK-1, one of the key regulators in glucose breakdown, were significantly increased in adipose tissue in all three rat models.
Pyruvate dehydrogenase beta and citrate synthase, critical enzymes in energy metabolism, were elevated in the MCT and SuHx models, with a non-significant trend in the hypoxic rat model.
Finally, significantly elevated production of CD36, which facilitates fatty acid uptake in adipose tissue, was seen in all three rat models, compared to controls. Similar results were observed in other enzymes involved in fatty acid breakdown.
“In summary, we report a pattern of dysregulated adipokine circulating levels in humans with idiopathic pulmonary arterial hypertension,” the researchers wrote. “Our findings in adipose tissue in three experimental models, support that adipose tissue may be contributing to PAH pathogenesis via adipokine release and altered bioenergetics.”
“Consistent with the notion that PAH is a systemic disease, we report for the first time adipose tissue metabolic alterations in experimental models,” they added. “Additional studies to identify the cellular sources of these adipokines, both within the lung and within adipose tissue, are needed in order to gain mechanistic insights into their potential role in disease pathogenesis.”
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