Unacylated Ghrelin Fragment UAG(6-13) Reduced Myocardial Infarct Area 54% in Mice
Background
Unacylated ghrelin (UAG) is the most abundant circulating form of the hormone ghrelin and has shown promise for its cardioprotective effects in experimental models of heart disease. While its benefits are known, the specific mechanisms and the potential of its smaller, more stable fragments remained underexplored. Researchers hypothesized that a linear bioactive fragment of UAG could offer similar or even superior therapeutic benefits against myocardial ischemia/reperfusion injury, a common cause of heart damage following events like a heart attack. This injury involves a complex cascade of inflammation and cell death that current treatments only partially mitigate. The study investigated a specific fragment, UAG(6-13), to determine if it could protect the heart, improve function, and elucidate the molecular pathways involved, particularly its independence from the classical ghrelin receptor, GHSR1a.
Study Design
C57BL/6 wild-type mice were pre-treated for 14 days with either unacylated ghrelin (100 nmol/kg) or the fragment UAG(6-13) at two doses (1,000 and 3,000 nmol/kg), administered every 12 hours. Following this pre-treatment period, the mice underwent a 30-minute ligation of the left coronary artery to induce myocardial ischemia, followed by a reperfusion period of either 6 or 48 hours. Researchers then measured the infarct area, assessed myocardial hemodynamics, and measured circulating levels of pro-inflammatory cytokines like IL-6 and TNF-α. The involvement of the classical ghrelin receptor (GHSR1a) was tested in isolated hearts using the antagonist D-Lys3-GHRP-6.
Results
The UAG(6-13) fragment demonstrated significant cardioprotective effects. The highest dose tested (3,000 nmol/kg) reduced the infarct area in a dose-dependent manner. Myocardial hemodynamics showed marked improvement, evidenced by increases in cardiac output, the maximum first derivative of left ventricular pressure, and preload recruitable stroke work, a load-independent measure of contractility. The treatment also suppressed inflammation, reducing circulating levels of IL-6 and TNF-α at 6 hours post-reperfusion, with the effect on TNF-α sustained at 48 hours. Mechanistically, the peptide activated 5' AMP-activated protein kinase (AMPK) and inhibited acetyl-CoA carboxylase (ACC), while also decreasing levels of apoptotic proteins. Crucially, the effects of UAG(6-13) were not blocked by a GHSR1a antagonist, confirming the action is independent of the classical ghrelin receptor.
After 48 hours of reperfusion, the highest dose of UAG(6-13) achieved a 54% reduction in the myocardial infarct area.
Key Findings
- The highest dose of UAG(6-13) (3,000 nmol/kg) reduced myocardial infarct area by 54% at 48 hours of reperfusion.
- Treatment improved myocardial hemodynamics, including cardiac output and left ventricular pressure.
- Circulating pro-inflammatory cytokines IL-6 and TNF-α were reduced at 6 hours post-reperfusion.
- The cardioprotective effects were independent of the classical ghrelin receptor, GHSR1a.
- The peptide activated the AMPK pathway and inhibited ACC activity, reducing apoptotic protein levels.
Why It Matters
This study identifies UAG(6-13) as a potent, novel therapeutic agent for protecting the heart from ischemia-reperfusion injury. For researchers and clinicians, this finding opens a new avenue for developing treatments for heart attack patients, distinct from conventional ghrelin-based therapies that target the GHSR1a receptor. The fact that this smaller, linear fragment is effective suggests it may have advantages in stability and manufacturing over the full-length UAG peptide. The key takeaway is that ghrelin's cardioprotective signaling is not exclusively mediated by the GHSR1a receptor, and potent effects can be achieved with specific fragments. While this is an early-stage animal study, it provides a strong rationale for further preclinical development to establish dosing, safety, and efficacy profiles before any human trials could be considered. It points toward a future where specific peptide fragments could be used to mitigate cardiac damage.
