What Is B7-33 Peptide?
B7-33 is a soluble synthetic single-chain peptide obtained from the larger, naturally occurring protein H2-relaxin, which has pleiotropic actions, impacting the musculoskeletal system, cardiovascular system, and reproduction. It retains the anti-fibrotic properties of relaxin without enhancing cAMP production, stimulates ERK1/2 phosphorylation, and promotes matrix metalloproteinase 2 (MMP2) expression and the degradation of extracellular collagen.
The relaxin family peptides have four endogenous receptors divided into two pairs (RXFP1/2 and RXFP3/4). The function of these receptors is outlined as follows:
RXFP-1: Influences sperm motility, pregnancy, vascular endothelium, and joint health.
RXFP-2: Affects testicular descent.
RXFP-3: Mutations of this receptor affect schizotypal personality disorder and certain sleep disturbances.
RXFP-4: The role of this receptor is not clear. It is known to be expressed on sperm and alters insulin-like peptide 5, which in turn regulates hunger/satiation signaling.
The relaxin receptors are stimulated by cAMP, orexin, corticotropin-releasing factor (CRF), several insulin-like peptides, and GLP-1. The agonists exhibit anti-inflammatory, antioxidant, and wound healing properties. Research highlights that relaxin has all the properties apart from vasodilator, blood vessel growth stimulator, and antihypertrophic. Therefore, the peptide and its derivatives can be used in acute heart failure and other fibrotic disorders.
AKA: (B7-33)H2, GTPL9321
B7-33 preferentially stimulates the pERK pathway over the cAMP pathway. The pERK pathway regulates cell cycle arrest in the G1 phase and has been implicated in several diseases like Alzheimer’s and Crutzfeld-Jacob.
By blocking cell cycle progression in cells with RXFP1 receptors, B7-33 exercises its anti-fibrotic effects through the ability to stimulate RXFP1-angiotensin II type 2 receptor heterodimering, which activates pERK1/2 signaling and thus triggers the increased production of the collagen-degrading enzyme matrix metalloproteinase (MMP) -2.
Ease of Production
B7-33 is easier to produce and is more economical. It has less complicated 2D and 3D structures; it is easier to produce a functional B7-33 protein than a full H2-relaxin protein.
Fibrosis involves scarring or unorganized tissue regeneration and is the end state of at least half of all chronic diseases. In 2012, H2-relaxin completed phase II clinical trials to treat acute heart failure. The research revealed that H2-relaxin administration leads to instant vasodilation and reduces the long-term scarring seen following heart damage. This makes H2-relaxin the first new treatment approved for acute heart failure in 20 years.
Using the full relaxin protein as a therapeutic agent is challenging. H2-relaxin is difficult to produce and can only be administered via IV injection. It also increases heart rate and promotes cancer progression (particularly prostate cancer).
B7-33, the peptide increases MMP-2 production slightly more than H2-relaxin does. This significantly reduces cardiac fibrosis in rat models of MI-induced heart failure and improves cardiac function. Similar effects were recorded in mouse models of asthma and lung fibrosis.
Further, B7-33 overcame tumor growth even when administered at higher doses than those producing anti-fibrotic effects. It works almost exclusively through the pERK pathway and does not stimulate cAMP production.
Blood Vessel Protection
Human relaxin-2 (serelaxin) is relevant as it protects the vasculature against endothelial dysfunction and long-term scarring. B7-33 replicates the vasoprotective effects of serelaxin by enhancing bradykinin-mediated endothelium-dependent relaxation in arteries by boosting endothelium-derived hyperpolarization in certain vascular beds. The selectivity of this molecule in causing vasorelaxation can be useful in certain cardiovascular conditions and preeclampsia during pregnancy.
B7-33 in Preeclampsia
Preeclampsia is a common complication of pregnancy that leads to high blood pressure and reduced fetal weight. While manageable to a large degree, preeclampsia can be difficult to control and, in some cases, life-threatening to both mother and fetus. In the most extreme cases of preeclampsia, immediate delivery of the baby is necessary, making it a common cause of pre-term delivery. Research, however, suggests that relaxin and thus B7-33 may prove useful in controlling preeclampsia even in severe cases.
B7-33 binds to the RXFP-1 receptor to increase VEGF production in cytotrophoblasts. These cells, found in the developing fetus, are crucial to establishing blood flow between the maternal circulation and the developing fetus. By triggering VEGF production, B7-33 promotes the growth of blood vessels and thus improves the blood supply between mother and child.
Studies reveal that lipidated B7-33 has a prolonged in vivo half-life and that lipidation does not affect the activity of the peptides. A longer half-life would make B7-33 an even more effective therapeutic.
B7-33 in Anti-Fibrotic Materials
B7-33 finds application in producing anti-fibrotic materials or materials that resist the foreign body response. Fibrosis becomes problematic for implanting a medical device, like a cardiovascular stent, into the body. In these cases, fibrosis can lead to dysfunction or degradation of the implant and even lead to artery occlusion, reduced blood supply, and eventually a heart attack.
B7-33 offers an ideal coating for use in implants. Research has shown that the release of B7-33 from the coating of a device reduced fibrotic capsule thickness by nearly 50% over a 6-week trial and opened up the possibility of a range of improved implantable medical devices. The use of B7-33 and similar peptides could avoid the use of systemic substances (e.g., Plavix or aspirin when cardiac stents are placed) to reduce fibrosis of implanted medical devices. This reduction makes the devices safer and allows them to be implanted in a wider range of patients (e.g.patients with more severe disease).
B7-33 is a novel peptide with potent anti-fibrotic effects. It is actively studied to reduce fibrosis in acute and chronic diseases like heart failure and lung inflammation. The peptide has reduced fibrosis by roughly 50% in animal studies, leading to prolonged survival following injury and one of the first few offerings for treating heart failure in 20 years. The peptide holds the potential to reduce fibrosis and the rejection of implanted medical devices.
B7-33 further reduces blood pressure and protects vasculature, being of greatest interest. Studies in animal models of preeclampsia suggest that the peptide might be useful in treating this difficult-to-manage disease, potentially allowing more women to carry children to term in a safe manner for both mother and baby.