Signaling
A synthetic tetrapeptide (Ala-Glu-Asp-Arg) studied in preclinical models of myocardial tissue culture, peptide–chromatin interaction biochemistry, and gene-expression regulation.
Cardiogen is a synthetic tetrapeptide with the amino acid sequence Ala-Glu-Asp-Arg (AEDR), belonging to the class of short peptide bioregulators associated with research by V. Kh. Khavinson and colleagues at the St. Petersburg Institute of Bioregulation and Gerontology. In the published literature it has been examined in cell-culture and animal-model systems, where investigators measured proliferation indices, apoptosis-associated markers, cytoskeletal and nuclear-matrix protein expression, and peptide–DNA and peptide–histone interactions. The body of work is preclinical and concentrated within a single research network.
Type
Synthetic linear tetrapeptide (short peptide bioregulator)
Molecular formula
C18H31N7O9
Molecular weight
489.5 g/mol
Amino acids
4
Sequence
Ala-Glu-Asp-Arg (AEDR); systematic form H-Ala-Glu-Asp-Arg-OH
Modification
None (unmodified free peptide: free N-terminus, free C-terminus)
Cardiogen belongs to the class of ultra-short regulatory peptides (2–4 residues) termed peptide bioregulators. Its sequence contains acidic residues (Glu, Asp) and a basic residue (Arg), giving it a charged, amphiphilic character proposed to support interaction with nucleic acids and nuclear proteins. The mechanistic hypothesis examined for this peptide class is that short peptides can enter cells and the nucleus without a classical carrier and interact site-specifically with DNA — including methylated CNG/CG-containing sequences — and with N-terminal regions of histones, thereby influencing the accessibility of gene-promoter regions and the activity of DNA-processing enzymes. In structural and biophysical work, short peptides of this class have been modeled as binding the minor groove of double-stranded DNA. These proposals are derived from in vitro and in silico systems; the precise promoter sequences engaged by AEDR in cardiac cells have not been fully characterized in the published literature.
Research Focus
Studied in preclinical models of cardiac tissue culture, peptide–chromatin interaction biochemistry, and gene-expression regulation.
Cardiogen is the cardiac-associated member of the family of short peptide bioregulators developed within the research program of V. Kh. Khavinson and colleagues at the St. Petersburg Institute of Bioregulation and Gerontology. It is defined by the tetrapeptide sequence Ala-Glu-Asp-Arg (AEDR) and shares the Ala-Glu-Asp core motif with several related peptides in this class. The composition and experimental cardiac-pathology contexts of the AEDR tetrapeptide are documented in a US patent (Khavinson, Ryzhak, Grigoriev & Ryadnova, 2010), which lists the molecular formula C18H31N7O9 and molecular weight 489.48, and describes the animal model systems — including experimental myocardial infarction via coronary artery ligation, isolated perfused heart under ischemia, adrenaline-induced myocardial dystrophy, toxicochemical cardiomyopathy, and chemically induced arrhythmia in rats — in which the tetrapeptide was studied.
The most directly relevant primary study (Chalisova et al., 2009) examined AEDR in organotypic myocardial explant cultures from young and aged rats, measuring a proliferation/cell-composition index and an apoptosis-associated marker. The study compared the tetrapeptide response against those of the individual constituent amino acids in the same explant model, with p53 immunohistochemistry employed as the apoptosis-associated readout. Related earlier organotypic work (Zakutskii, Chalisova et al., 2006) examined cardiogen alongside other tissue-specific bioregulator peptides in explant cultures from heart, lung, prostate, and pancreas from young and aged rats, comparing tissue-specific effects across organ models.
Khavinson et al. (2012) examined H-Ala-Glu-Asp-Arg-OH in cultured mouse embryonic fibroblasts, measuring expression of cytoskeletal proteins (actin, tubulin, vimentin) and nuclear-matrix proteins (lamin A and lamin C) by immunofluorescence. The study framed the protein-expression measurements as a candidate molecular basis for cytoskeletal and nuclear-matrix synthesis activity associated with the peptide in earlier cardiac research. This is a cell-culture protein-expression measurement and not a human or in vivo functional outcome.
Several biochemical studies place AEDR within a panel of short peptides used to probe nuclear penetration and direct interaction with chromatin components. Fedoreyeva, Kireev, Khavinson & Vanyushin (2011) used fluorescently labeled short peptides to examine penetration into the cytoplasm, nucleus, and nucleolus of cultured cells, and measured in vitro interaction with deoxyribooligonucleotides and DNA. Fedoreyeva, Smirnova, Kolomijtseva, Khavinson & Vanyushin (2013) included Ala-Glu-Asp-Arg among a panel of short peptides and measured binding to wheat histones H1, H2B, H3, and H4 at their N-terminal regions, and to histone–deoxyribooligonucleotide complexes, using fluorescence-quenching methods. Khavinson, Fedoreyeva & Vanyushin (2011) examined in vitro whether short peptides modulate the hydrolysis of λ-phage DNA by eukaryotic endonucleases (WEN1 and WEN2) as a function of DNA methylation status. Structural modeling work (Khavinson, Tarnovskaya et al., 2013) used molecular-mechanics docking to build three-dimensional models of short peptide–DNA complexes, examining hydrogen-bond and electrostatic interaction geometries and minor-groove localization at specific promoter sequences; much of the detailed modeling has focused on related peptides in this class, with AEDR appearing as part of the broader peptide panel. These studies support the general mechanistic hypothesis for the short bioregulator class rather than an AEDR-specific cardiac mechanism.
Levdik & Knyazkin (2009) examined cardiogen in rats bearing transplanted M-1 sarcoma, measuring tumor-cell apoptosis level, proliferative-activity parameters, and tumor morphology. The study assessed the relationship between these measurements and cytostatic versus vascular mechanisms in this animal model. This study is the principal non-cardiac context in which the peptide has been examined.
The published Cardiogen-specific literature is small and concentrated almost entirely within the Khavinson research network and associated Russian-language journals — notably Advances in Gerontology (Uspekhi Gerontologii) and the Bulletin of Experimental Biology and Medicine. Several mechanistic findings are derived from peptide-panel studies where AEDR appears alongside other short bioregulators rather than being examined in isolation. No registered human clinical trials specific to the defined tetrapeptide AEDR were identified in ClinicalTrials.gov or the indexed literature. Independent replication of the cardiac-specific findings outside this network is limited, and these constraints should be weighed when interpreting the mechanistic hypotheses.
Lyophilized
Store sealed and protected from light, frozen (−20 °C, or colder for long-term storage), and desiccated.
Reconstituted
Refrigerate (2–8 °C) for short-term use
freeze in single-use aliquots for longer-term storage. Avoid repeated freeze–thaw cycles.
As a small unmodified linear peptide with charged residues, susceptible to proteolysis and degradation from heat, light, and repeated freeze–thaw. Handle using standard aseptic technique. For research use only.
Reviews
Khavinson VK, Popovich IG, Linkova NS, Mironova ES, Ilina AR (2021). Molecules — Systematic review of short-peptide regulation of gene expression via peptide–DNA and peptide–histone interaction mechanisms
Khavinson VKh, Lin'kova NS, Tarnovskaya SI (2016). Bulletin of Experimental Biology and Medicine — Review of molecular mechanisms by which short peptides regulate gene expression, including cell penetration and DNA docking
Primary research
Fedoreyeva LI, Smirnova TA, Kolomijtseva GY, Khavinson VKh, Vanyushin BF (2013). Biochemistry (Moscow) — In vitro biochemical study of short peptides (including AEDR) binding wheat histones and histone–oligonucleotide complexes
Primary research
Khavinson VKh, Tarnovskaya SI, Linkova NS, Pronyaeva VE, Shataeva LK, Yakutseni PP (2013). Bulletin of Experimental Biology and Medicine — In silico molecular-mechanics modeling of short cell-penetrating peptide interactions with gene-promoter DNA sites
Khavinson VKh, Lin'kova NS, Polyakova VO, Kvetnoy IM, Benberin VV, D'yakonov MM, Titkov YS (2012). Bulletin of Experimental Biology and Medicine — Cell-culture protein-expression study of H-Ala-Glu-Asp-Arg-OH on cytoskeletal and nuclear-matrix proteins in mouse embryonic fibroblasts
Fedoreyeva LI, Kireev II, Khavinson VKh, Vanyushin BF (2011). Biochemistry (Moscow) — In vitro study of nuclear penetration of short fluorescence-labeled peptides in cultured cells and their interaction with deoxyribooligonucleotides
Khavinson VKh, Fedoreyeva LI, Vanyushin BF (2011). Bulletin of Experimental Biology and Medicine — In vitro study of site-specific short peptide–DNA binding modulating eukaryotic endonuclease activity by DNA methylation status
Khavinson VKh, Ryzhak GA, Grigoriev EI, Ryadnova IYu (2010). United States Patent US 7,662,789 B2 — Patent documenting composition, synthesis, and experimental cardiac-pathology test models of the AEDR tetrapeptide
Levdik NV, Knyazkin IV (2009). Bulletin of Experimental Biology and Medicine — Animal-model study measuring tumor-cell apoptosis, proliferative-activity parameters, and tumor morphology after cardiogen administration in rats bearing transplanted M-1 sarcoma
Chalisova NI, Lesniak VV, Balykina NA, Urt'eva SA, Urt'eva TA, Sukhonos IuA, Zhekalov AN (2009). Advances in Gerontology — Organotypic myocardial tissue-culture study measuring proliferation index and p53 immunostaining in young and aged rat explants exposed to cardiogen
Zakutskii AN, Chalisova NI, Ryzhak GA, Aniskina AI, Filippov SV, Zeziulin PN (2006). Advances in Gerontology — Organotypic tissue-culture study of tissue-specific bioregulator peptides in heart, lung, prostate, and pancreas explants from young and aged rats
Research Use Only
These products are intended for research purposes only and are not for human consumption. Not FDA approved. Not intended to diagnose, treat, cure, or prevent any disease.
