Study reveals link between protein in skeletal muscle and PH-HFpEF

A lack of SIRT3 triggered release of LOXL2, which promotes lung tissue scarring

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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A SIRT3 protein deficiency in skeletal muscles, which are attached to bones, was related to pulmonary hypertension associated with heart failure with preserved ejection fraction (PH-HFpEF), a study shows.

A lack of SIRT3 triggered the release of LOXL2, a protein that promotes lung tissue scarring, which stimulated the CNPY2 pathway related to the thickening of pulmonary arteries and PH. Suppressing LOXL2 improved PH signs in a mouse model.

The findings identify skeletal muscle SIRT3, LOXL2, and CNPY2 in the pulmonary vasculature as potential molecular targets for developing PH-HFpEF therapies, a research team led by scientists at the Indiana University School of Medicine wrote in “Skeletal Muscle SIRT3 Deficiency Contributes to Pulmonary Vascular Remodeling in Pulmonary Hypertension Due to Heart Failure With Preserved Ejection Fraction,” which was published in Circulation.

PH is a major complication in heart failure with preserved ejection fraction (HFpEF), which is when patients have heart failure, but the percentage of blood pumped out of the left ventricle with each heartbeat is normal or near normal. PH in HFpEF develops due to stiffness in the muscles of the left side of the heart and an inability to meet the body’s demands.

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SIRT3 and PH-HFpEF severity

Using a rat model of PH-HFpEF, researchers discovered decreased levels of the enzyme SIRT3 (Sirtuin 3) in skeletal muscles, which are attached to bones and are responsible for voluntary movements.

What stood out, however, was that SIRT3 levels were normal in the muscles of the heart and the pulmonary arteries. Also, restoring SIRT3 in skeletal muscle reduced PH-HFpEF severity, “indicating a critical role of skeletal muscle SIRT3 in regulating pulmonary vascular remodeling and PH-HFpEF,” said the researchers, who selectively deleted SIRT3 from the skeletal muscles of mice and assessed PH-related parameters and tissues to better understand the connection between SIRT3 and PH-HFpEF.

Without SIRT3, mice had elevated pulmonary blood pressure, increased pulmonary vascular remodeling, and fewer pulmonary arteries per area of lung tissue.

Molecular experiments revealed that SIRT3-deficient skeletal muscle cells secreted LOXL2, a protein that promotes lung tissue scarring and drives lung diseases like idiopathic pulmonary fibrosis (IPF). In fact, LOXL2 is a potential biomarker and a therapeutic target for IPF. At the same time, LOXL2 was significantly higher in the bloodstream of mice without SIRT3 and a rat model of PH-HFpEF.

More importantly, people with PH-HFpEF had elevated levels of LOXL2 in their bloodstream compared with unaffected people. Consistently, muscle biopsies of PH-HFpEF patients had higher LOXL2 production alongside reduced SIRT3, compared to HFpEF patients without PH.

Treating lung tissue isolated from mice with lab-made LOXL2 triggered the increase of several proteins, particularly CNPY2, which was also significantly elevated in the lungs of a rat model of PH-HFpEF. CNPY2 has recently been identified as an initiator of the unfolded protein response pathway, a protein quality-control mechanism, and was found to promote tumor growth.

LOXL2 treatment also significantly increased CNPY2 in cultured human pulmonary artery endothelial cells (PAECs), which line the arteries, and pulmonary artery smooth muscle cells (PASMCs), which surround and provide structure to PAECs. Furthermore, LOXL2, via the CNPY2 pathways, stimulated PAEC migration and the growth of both PAECs and PASMCs.

Lastly, the researchers selectively deleted LOXL2 from mice skeletal muscles. To induce PH-HFpEF, the mice were fed a high-fat diet, which reduces SIRT3 in skeletal muscle and leads to developing PH-HFpEF associated with metabolic syndrome, a group of risk factors specific to cardiovascular disease.

Mice lacking skeletal muscle-secreted LOXL2 had decreased CNPY2 and eased PH, results showed. Consistent with these data, blocking LOXL2 with a small molecule also eased PH signs via CNPY2 in PAECs and PASMCs, compared with mice fed with a high-fat diet alone.

“Our studies have uncovered several processes by which skeletal muscle SIRT3 deficiency can affect pulmonary vascular health in PH-HFpEF,” the researchers said. “Our findings also provide new insights into the mechanistic basis of the skeletal muscle-lung communication and identify skeletal muscle SIRT3, [LOXL2], and CNPY2 in the pulmonary vasculature as potential molecular targets for the development of therapeutic treatments in PH-HFpEF.”

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