Keerthana Prayaga

Background: Heart failure is a significant health problem in the United States affecting over 6.5 million US adults¹. Many newly introduced therapeutics have not been successful past preclinical trials and survival rates have stagnated despite existing therapies^1,2. Failing cardiomyocytes are characterized by decreased cardiac performance, arrhythmias, tissue necrosis, inflammation, and decreased mitochondrial function. S100A1 is a naturally occurring cardiac peptide that binds calcium and positively regulates cardiomyocyte performance through targeting pathways implicated in heart failure^1,2,3. S100A1 expression is reduced in failing cardiomyocytes; therefore, researchers are exploring ways to supplement S100A1 to improve cardiac function⁴. Given the suboptimal efficiency of current cardiac targeting vectors, scientists are exploring peptide-based therapeutics to effectively deliver S100A1⁵. This review explores recent advances of S100A1’s therapeutic potential in heart failure.

Objective: This narrative review explored S100A1 as a target for peptide therapeutics in failing hearts, focusing on the mechanisms through which S100A1 benefits contractile performance, mitochondrial function, antiarrhythmic and anti-inflammatory properties, and combats myocardial necrosis.

Search Methods: An online PubMed search for primary research articles and reviews published between 2018 and 2025 using keywords “heart failure”, “peptide delivery”, and “S100A1” was conducted.

Results: Studies showed that failing rat cardiomyocytes treated with a synthetic S100A1 replica (S100A1ct) displayed significant improvements in calcium amplitude, sarcoplasmic reticulum (SR) calcium content, and fractional shortening⁴. This indicates stronger contractile performance and depends on S100A1’s binding of the calcium channel SERCA2A, which allows for improved calcium uptake by SR and diastolic relaxation that leads to stronger systolic contractions. S100A1-treated cardiomyocytes displayed heightened SERCA2A activity⁴. Additionally, these cardiomyocytes showed increased F1ATPase activity, improving ATP production⁴. Improved mitochondrial respiration elevates mitochondrial performance and heightened mitochondrial organization upon treatment of failing cardiomyocytes with S100A1⁶. Cardiomyocytes treated with S100A1 post-MI injury displayed decreased levels of inflammatory cytokines IFN-gamma, IL-13, and IL-17and lipid reactive oxygen species (MDA, HNE), indicating less inflammation⁶.  AMPK/ACC pathway activation, which is heightened due to metabolic stress, was decreased upon S100A1 treatment⁷. Following S100A1 treatment, cardiomyocytes displayed decreased levels of myocardial necrosis markers troponin t and lactate dehydrogenase⁷. Upon S100A1ct treatment, both normal rat and failing human cardiomyocytes displayed significant decreases in calcium sparks and diastolic after contractions which are indications of arrhythmias due to calcium leakage through the Ryanodine Receptor 2 (RYR2) channel in SR after systolic contraction⁴. S100A1 binds and regulates RYR2⁴. The C85 moiety of S100A1 is implicated in binding RYR2 as cardiomyocytes treated with C85 deficient S100A1 had an increase in after contraction calcium waves⁸. A specific Cardiac Targeting Peptide (CTP) created by researchers proved to be an effective cardiac vector with maximal uptake by cardiomyocytes occurring 15 minutes after treatment, indicating high efficiency compared to existing options⁵. Treatment with CTP-conjugated S100A1ct in both normal and failing rat cardiomyocytes improved contractile properties, indicating potential for an efficient delivery mechanism⁴.

Conclusions: S100A1 improves contractile performance by regulating SERCA2A, allowing for diastolic relaxation as well as mitochondrial function and mitochondrial energy production. S100A1-treated cells have less activation of metabolic stress pathways and lower expression of inflammatory cytokines. S100A1 prevents arrhythmias by regulating RYR2, decreasing systolic after contractions that contribute to arrhythmias. Enhanced delivery of S100A1ct is demonstrated upon conjugation with CTP, indicating potential for therapeutic delivery potential in heart failure. Considering S100A1 as a potential target and expanding investigation into its systemic effects is therefore warranted.

Works Cited :

1. Murphy SP, Ibrahim NE, Januzzi JL. Heart Failure With Reduced Ejection Fraction. JAMA. 2020;324(5):488-504. doi:https://doi.org/10.1001/jama.2020.10262
2. Jakub Rosik, Szostak B, Machaj F, Pawlik A. Potential targets of gene therapy in the treatment of heart failure. Expert Opinion on Therapeutic Targets. 2018;22(9):811-816. doi:https://doi.org/10.1080/14728222.2018.1514012
3. Zhihao L, Jingyu N, Lan L, et al. SERCA2a: a key protein in the Ca2+ cycle of the heart failure. Heart Failure Reviews. 2019;25(3):523-535. doi:https://doi.org/10.1007/s10741- 019-09873-3
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8. Seitz A, Busch M, Kroemer J, et al. S100A1’s single cysteine is an indispensable redox switch for the protection against diastolic calcium waves in cardiomyocytes. Am J Physiol Heart Circ Physiol. 2024;327(1):H000. doi:10.1152/ajpheart.00634.2023