Stroke, Heart Attack Damage Could Be Mitigated via Mimicry of Good Cholesterol

It may be a caricature, but it is recognized by ailing blood vessels, which respond by moving closer to a picture of cardiovascular health. The “it” is an artificial protein called ApoM-Fc that mimics apolipoprotein M (ApoM), a natural protein that is a component of high-density lipoprotein (HDL), or “good cholesterol.” ApoM-Fc performs better than synthetically derived ApoM, which is expensive to produce and has just a 15-minute half-life in the body’s bloodstream. In tests on mice, ApoM-Fc lowered blood pressure and alleviated tissue damage caused by stroke, heart attack, and other cardiovascular diseases.

ApoM-Fc, like ApoM, ferries S1P, or sphingosine-1-phosphate, particles through the bloodstream to endothelial cells, which line the blood vessels and are studded with S1P receptors. When these receptors recognize S1P, and bind them, endothelial cells work to suppress inflammation, thereby promoting cardiovascular health. Unfortunately, S1P doesn’t work on its own. It needs a chaperone, a sort of carrier.

The artificial S1P carrier was engineered by scientists based at Boston Children’s Hospital Vascular Biology Program. These scientists, led by Timothy Hla, Ph.D., showed that their novel protein could trigger increased S1P receptor activity and recover blood vessel health.

Details of the scientists’ work appeared August 15 in the journal Science Signaling, in an article entitled “An Engineered S1P Chaperone Attenuates Hypertension and Ischemic Injury.” The article noted that while HDL is known to alleviate endocardial dysfunction, globally increasing HDL abundance is not beneficial, suggesting that “specific HDL species mediate protective effects.” The article also indicated that the Boston Children’s team decided to focus on ApoM-positive HDL.

“We report the development of a soluble carrier for S1P, ApoM-Fc, which activated S1P receptors in a sustained manner and promoted endothelial function,” wrote the article’s authors. “ApoM-Fc administration reduced blood pressure in hypertensive mice, attenuated myocardial damage after ischemia/reperfusion injury, and reduced brain infarct volume in the middle cerebral artery occlusion model of stroke.”

The authors also emphasized that ApoM-Fc did not modulate circulating lymphocyte numbers, suggesting that it specifically activated endothelial S1P receptors.

“HDL carries a protein called ApoM, which in turn attracts and binds S1P in its cargo,” explained Dr. Hla, the senior author on the new paper. “Together, this trio activates S1P receptors and promotes endothelial cell function and, ultimately, blood vessel repair.”

But, mimicking this trio in a therapeutic derivation would not be as straightforward. HDL, a highly complex and large nanoparticle decorated with a plethora of proteins and lipids in addition to ApoM, is very difficult to synthesize and produce in the lab. So, Dr. Hla strategized on how to optimize ApoM, the linker protein between HDL and S1P.

To make a therapeutic impact and deliver more S1P to their receptors, Dr. Hla decided that a long-lasting version of ApoM would be desirable. Consequently, Dr. Hla’s team took a cue from the immune system. They adapted a highly-stable antibody fragment called Fc, or fragment crystallizable, and fused it to synthetic ApoM.

To test its therapeutic efficacy, Dr. Hla and his team gave their engineered ApoM-Fc in combination with S1P to groups of mice with different models of vascular disease and injury. Together, the ApoM-Fc fusion had a staggeringly longer half-life than ApoM alone, lasting for up to 90 hours within the bloodstream. Inside the mice’s blood, ApoM-Fc robustly activated S1P receptors on the blood vessel’s endothelial cells. Strikingly, the therapeutic combination of ApoM-Fc and S1P reduced blood pressure in hypertensive mice, mitigated tissue damage from heart attack, and boosted brain tissue recovery after stroke.

“If you provide engineered ApoM-Fc with S1P, we see a clear therapeutic benefit in preclinical animal models,” asserted Dr. Hla. “In mice, it allowed blood vessels to better repair themselves after various types of disease and injury—so we are eager to see if this is something that could one day translate into the clinic.”