S100A1 Human
Description
Expression and Localization in Human Tissues
S100A1 exhibits a distinct tissue distribution pattern in humans, with highest expression levels observed in cardiac and skeletal muscle tissues . Significant expression is also detected in the brain and kidney . This specific expression pattern suggests specialized roles in these tissues, particularly in regulating muscle function and calcium homeostasis.
At the subcellular level, S100A1 predominantly localizes to specific compartments within muscle cells. In cardiomyocytes, S100A1 mainly resides on the sarcoplasmic reticulum (SR), mitochondria, and myofilaments . More specifically, S100A1 localizes to the Z-discs and SR in both cardiac and skeletal muscle . This strategic positioning allows S100A1 to interact with and regulate key calcium-handling proteins and energy metabolism components.
During embryonic development, S100A1 expression follows a defined temporal and spatial pattern. In the primitive heart, S100A1 is expressed at embryonic day 8 with similar levels between atria and ventricles . As development progresses to embryonic day 17.5, S100A1 expression shifts to lower levels in atria and higher levels in ventricular myocardium . This developmental regulation suggests an important role in cardiac maturation and function.
S100A1 Expression Levels in Human Tissues
| Tissue Type | Relative Expression Level | Key Subcellular Locations |
|---|---|---|
| Cardiac Muscle | Very High | Sarcoplasmic reticulum, Z-discs, mitochondria, myofilaments |
| Skeletal Muscle | High | Sarcoplasmic reticulum, Z-discs, mitochondria |
| Brain | Moderate | Neuronal cells |
| Kidney | Moderate | Not fully characterized |
| Other Tissues | Low to Negligible | Various |
Functional Mechanisms of S100A1
S100A1 performs numerous cellular functions primarily through calcium-dependent interactions with target proteins. Its ability to bind calcium and undergo subsequent conformational changes enables S100A1 to recognize and modulate the activity of a diverse array of molecular targets .
Molecular Targets and Interactions
Research has identified an extensive list of proteins that interact with S100A1. Key targets include :
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Calcium signaling proteins: Ryanodine receptors 1 & 2 (RyR1, RyR2), sarcoplasmic reticulum Ca²⁺ ATPase (SERCA2a), phospholamban (PLB)
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Cytoskeletal and filament associated proteins: CapZ, microtubules, intermediate filaments, tau, microfilaments, desmin, tubulin, F-actin, titin, glial fibrillary acidic protein (GFAP)
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Transcription factors and their regulators: myoD, p53
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Enzymes: Aldolase, phosphoglucomutase, malate dehydrogenase, glycogen phosphorylase, photoreceptor guanyl cyclases, adenylate cyclases, glyceraldehydes-3-phosphate dehydrogenase, twitchin kinase, Ndr kinase, F1 ATP synthase
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Other Ca²⁺-activated proteins: Annexins V & VI, S100B, S100A4, S100P, and other S100 proteins
These interactions underpin the multifaceted roles of S100A1 in cellular physiology, particularly in regulating calcium homeostasis, energy metabolism, and contractile function.
Regulation of Calcium Handling
S100A1 plays a critical role in regulating myocyte calcium cycling through interactions with key calcium-handling proteins. In cardiomyocytes, S100A1 modulates the activity of:
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Ryanodine Receptors (RyR2): S100A1 interaction with RyR2 modulates calcium-induced calcium release, enhancing systolic calcium release while reducing pathological diastolic calcium leak .
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SERCA2a and Phospholamban: S100A1 enhances SERCA2a activity by approximately 30%, improving calcium reuptake into the sarcoplasmic reticulum during diastole . Knockout studies show a reciprocal ~30% decrease in calcium reuptake in S100A1-deficient muscles .
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L-Type Calcium Channels: S100A1 may enhance L-type calcium channel activity through protein kinase A activation, although some studies show contradictory results .
These mechanisms collectively improve calcium cycling efficiency, enhancing both systolic contractility and diastolic relaxation in cardiomyocytes.
Impact on Contractile Function
S100A1 directly influences myocardial contractility through multiple mechanisms:
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Enhancement of Excitation-Contraction Coupling: S100A1 increases the gain of excitation-contraction coupling while decreasing calcium spark frequency in cardiomyocytes .
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Modulation of Myofilament Properties: S100A1 decreases myofibrillar Ca²⁺ sensitivity ([EC 50%]) and Ca²⁺ cooperativity, optimizing force development without changing maximal isometric force .
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Titin Interaction: S100A1 binds to the PEVK region of titin in a calcium-dependent manner, potentially modulating titin-based passive tension prior to systole .
These effects translate to improved contractile performance, enhanced relaxation, and optimized force-frequency relationships in cardiac muscle.
Mitochondrial Function and Energy Metabolism
Beyond calcium handling and contractility, S100A1 significantly impacts energy metabolism:
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F1-ATPase Regulation: S100A1 enhances F1-ATP synthase activity in a dose-dependent manner, improving mitochondrial ATP production .
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Energy Homeostasis: S100A1 helps maintain proper phosphocreatine/adenosine-triphosphate (PCr/ATP) ratios, supporting optimal energy availability for contractile function .
These effects are particularly relevant for high-energy-consuming tissues like cardiac and skeletal muscle, ensuring adequate energy supply during periods of increased demand.
Role in Cardiovascular Physiology
S100A1 serves as a critical regulator of cardiac function under both normal and pathological conditions. Its roles span from myocardial contractility to vascular biology, making it a central player in cardiovascular physiology.
Regulation of Cardiac Contractility
Multiple studies have demonstrated S100A1's significant impact on cardiac contractile performance. In experimental models, S100A1 overexpression substantially improves both inotropic (contractility) and lusitropic (relaxation) states of isolated cardiac myocytes . These effects manifest as:
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Enhanced Contractile Force: S100A1 gene transfer results in significant increases in unloaded shortening and isometric contraction in isolated cardiomyocytes and engineered heart tissues .
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Improved Calcium Transients: Analysis of intracellular Ca²⁺ cycling in S100A1-overexpressing cardiomyocytes reveals significant increases in cytosolic Ca²⁺ transients .
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Enhanced SR Ca²⁺ Uptake: Functional studies on saponin-permeabilized adult cardiomyocytes show that S100A1 significantly enhances SR Ca²⁺ uptake .
These mechanisms operate in a cAMP-independent manner, as cellular cAMP levels and protein kinase A-dependent phosphorylation of phospholamban remain unaltered, and carbachol fails to suppress S100A1 actions .
Developmental Regulation
S100A1 expression is dynamically regulated during cardiac development. Expression begins in the primitive heart at embryonic day 8 with similar levels between atria and ventricles . As development progresses, S100A1 expression shifts to lower levels in atria and higher levels in ventricular myocardium by embryonic day 17.5 . This pattern suggests a role in the maturation of chamber-specific functions in the developing heart.
Vascular Effects
Beyond cardiomyocytes, S100A1 influences vascular function through effects on endothelial cells. In endothelial cells, S100A1 stimulates nitric oxide (NO) production by increasing endothelial nitric oxide synthase activity . Studies in S100A1 knockout mice reveal significantly elevated blood pressure values with abrogated responsiveness to vasodilatory agents like bradykinin , highlighting the importance of S100A1 in vascular tone regulation.
Pathological Implications in Human Disease
Alterations in S100A1 expression and function have been implicated in various human pathologies, most notably cardiovascular disorders but also extending to other conditions.
5.1.1 Heart Failure
One of the most significant pathological findings is the consistent reduction of S100A1 protein levels in failing myocardium. Studies of human heart failure samples demonstrate that S100A1 levels progressively decline as cardiac dysfunction worsens, with end-stage heart failure showing the most pronounced reduction . Importantly, left ventricular assist device-based therapy does not restore S100A1 levels in patients , suggesting that this molecular defect persists despite hemodynamic unloading.
In experimental models that recapitulate this S100A1 deficiency, mice lacking S100A1 (S100A1-/-) show impaired cardiac reserve upon beta-adrenergic stimulation, with reduced contraction and relaxation rates as well as reduced calcium sensitivity . Following myocardial infarction, S100A1 knockout mice exhibit accelerated transition towards heart failure and excessive mortality compared to wild-type controls .
5.1.2 Myocardial Infarction and Ischemia
S100A1 has emerged as a promising early diagnostic biomarker for acute myocardial ischemia. The protein shows a distinct time course in human plasma following an ischemic event, differentiating it from traditional markers like creatine kinase, CKMB, and troponin I . Interestingly, this injury-released, extracellular pool of S100A1 appears to serve a protective function, as it was shown to prevent apoptosis in neonatal murine cardiomyocytes via an ERK1/2-dependent pathway . This suggests that S100A1 release from injured cells represents an intrinsic survival mechanism for viable myocardium.
5.1.3 Cardiac Hypertrophy and Remodeling
S100A1 has been identified as a regulator of the genetic program underlying cardiac hypertrophy. Research indicates that S100A1 inhibits alpha1 adrenergic stimulation of hypertrophic genes, including MYH7, ACTA1, and S100B . Additionally, S100A1 protein levels are altered in right ventricular hypertrophied tissue in models of pulmonary hypertension , suggesting involvement in pressure-overload responses.
Cancer
Recent research has identified roles for S100A1 in certain cancers, particularly papillary thyroid carcinoma (PTC). Studies show that S100A1 is significantly upregulated in PTC tissues compared to adjacent non-cancerous tissues . S100A1 protein expression is significantly associated with tumor size (p=0.0032) and lymph node metastasis (p=0.0331) . Importantly, elevated S100A1 expression correlates with worse recurrence-free survival (HR=2.26, p=0.042) .
Functional studies demonstrate that knockdown of S100A1 dramatically inhibits cell proliferation and migration, while increasing apoptosis of PTC cells. Mechanistically, down-regulation of S100A1 induces yes-associated protein (YAP) phosphorylation in the cytoplasm and diminishes Hippo/YAP pathway activation . These findings suggest S100A1 may serve as an oncogene and potential biomarker for PTC diagnosis and prognosis.
Other Conditions
S100A1 levels are also altered in several other tissues in pathological states. Research has shown changes in S100A1 expression in the brain, skeletal muscle, and cardiac muscle in models of type I diabetes mellitus . Additionally, S100A1 has been identified as a biomarker for uncontrolled hyperoxic reoxygenation during cardiopulmonary bypass in infants with cyanotic heart disease and in adults .
Therapeutic Applications
The recognition of S100A1's critical roles in cellular function, particularly in the cardiovascular system, has prompted extensive research into its therapeutic potential. Several promising approaches have emerged from this work.
Gene Therapy for Heart Failure
Targeted repair of S100A1 deficiency through gene therapy represents one of the most promising therapeutic applications. Multiple studies in small and large animal heart failure models have demonstrated that S100A1 overexpression results in :
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Reversal of maladaptive myocardial remodeling
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Long-term rescue of contractile performance
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Superior survival in response to myocardial infarction
In a rat model of myocardial infarction, intracoronary S100A1 adenoviral gene transfer produced remarkable improvements, including :
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Restoration of sarcoplasmic reticular calcium transients and load
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Normalization of intracellular sodium concentrations
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Reversal of pathologic expression of the fetal gene program
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Restoration of energy supply
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Normalization of contractile function
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Preservation of inotropic reserve
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Reduction of cardiac hypertrophy
These benefits were observed just one week post-myocardial infarction, highlighting the rapid therapeutic potential of this approach.
S100A1ct Peptide-Based Therapeutics
A more recent and highly promising therapeutic approach involves S100A1ct, a synthetic peptide derived from the C-terminal α-helix (residues 75-94) of S100A1 protein . S100A1ct has been characterized as a cell-penetrating peptide with positive inotropic and antiarrhythmic properties in both normal and failing myocardium in vitro and in vivo .
Studies show that S100A1ct exerts a fast and sustained dose-dependent enhancement of cardiomyocyte Ca²⁺ cycling and prevents β-adrenergic receptor-triggered Ca²⁺ imbalances by targeting SERCA2a and RyR2 activity . Molecular modeling suggests that S100A1ct may stimulate SERCA2a by interacting with the transmembrane segments of this calcium pump .
The therapeutic efficacy of S100A1ct has been demonstrated in preclinical heart failure models with reduced ejection fraction, where systemic administration improved contractile performance and survival . Further enhancement has been achieved by incorporating a cardiomyocyte-targeting peptide tag into S100A1ct (cor-S100A1ct), which further increased its biological and therapeutic potency .
Tissue Engineering Applications
S100A1 gene transfer to engineered heart tissue has been shown to augment contractile performance of tissue implants . This suggests potential applications in cardiac tissue replacement therapy for heart failure patients, though the clinical efficacy of this strategy remains to be determined.
Pharmacological Interactions
Several existing drugs are known to bind S100A1, including pentamidine, amlexanox, olopatadine, cromolyn, and propranolol . While these interactions are generally of moderate affinity (mid-micromolar range), they suggest the possibility of developing more specific small-molecule modulators of S100A1 function for therapeutic purposes.
Future Research Directions
Research on human S100A1 continues to evolve rapidly, with several promising avenues for future investigation:
Clinical Translation of S100A1-Based Therapies
The transition from preclinical studies to human clinical trials represents a critical next step for S100A1-based therapies. Key areas of focus include:
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Optimization of gene delivery systems for S100A1 gene therapy in humans
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Pharmacokinetic and pharmacodynamic profiling of S100A1ct peptide therapeutics
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Development of targeted delivery approaches to maximize cardiac specificity and minimize off-target effects
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Establishment of appropriate patient selection criteria for S100A1-targeted interventions
Expanded Understanding of Pathophysiological Roles
Further research is needed to fully elucidate S100A1's roles in various pathological conditions:
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Cancer biology: Following the identification of S100A1's role in papillary thyroid carcinoma, investigation of its potential involvement in other cancer types may yield new diagnostic or therapeutic opportunities.
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Metabolic disorders: Given S100A1's effects on mitochondrial function and energy homeostasis, investigation of its potential roles in metabolic diseases could be informative.
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Neurodegenerative conditions: Considering S100A1's expression in the brain and its interaction with tau protein, investigation of potential roles in neurodegenerative disorders warrants exploration.
Development of S100A1-Targeted Diagnostics
The potential of S100A1 as a biomarker for cardiac pathologies deserves further development:
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Refinement of S100A1-based diagnostic assays for early detection of myocardial injury
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Integration with other cardiac biomarkers to improve diagnostic specificity and sensitivity
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Exploration of imaging approaches using labeled S100A1-targeting agents
Product Specs
Q&A
What is S100A1 and where is it expressed in human tissues?
S100A1 is a calcium-binding protein belonging to the S100 family, characterized by EF-hand structures. It is part of a cluster of at least 25 S100 proteins located on human chromosome 1q21 . S100A1 shows tissue-specific expression patterns, with highest abundance in the heart (particularly the left ventricle), followed by skeletal muscle, brain, and kidney . Within cardiac tissue, expression levels follow a gradient with highest concentrations in the left ventricle and lower levels in the right ventricle and atria . At the subcellular level, S100A1 predominantly localizes to the sarcoplasmic reticulum, mitochondria, and myofilaments in cardiomyocytes . This specific distribution pattern directly correlates with its functional roles in regulating calcium cycling, energy production, and contractile machinery.
How does S100A1 expression change in cardiac pathologies?
S100A1 expression exhibits distinct alterations in cardiovascular diseases. In heart failure, particularly following myocardial infarction, S100A1 protein levels become significantly depleted in failing cardiomyocytes . This reduction correlates with decreased contractile function and impaired calcium handling. Studies in S100A1 knockout mice revealed that absence of S100A1 accelerates the transition toward heart failure following myocardial infarction, resulting in excessive mortality compared to wild-type controls . These findings establish S100A1 downregulation as not merely a biomarker but a contributor to heart failure pathophysiology. Interestingly, normalization of S100A1 levels through gene therapy approaches in animal heart failure models has demonstrated reversal of maladaptive myocardial remodeling and enhanced survival , highlighting its potential as a therapeutic target.
What structural features characterize human S100A1 protein?
Human S100A1 is a 10.4 kDa protein comprising 94 amino acids (Met1-Ser94) . The protein functions as a homodimer and belongs to the EF-hand calcium sensor protein superfamily . Each monomer contains two distinct EF-hand calcium-binding motifs connected by a hinge region, with the C-terminal EF-hand displaying higher calcium affinity than the N-terminal one. Upon calcium binding, S100A1 undergoes a conformational change that exposes hydrophobic surfaces, enabling interaction with target proteins. The C-terminal α-helix (helix IV) is particularly significant, as synthetic peptides derived from this region (S100A1ct) can mimic and even enhance the functional effects of the full-length protein . X-ray crystallography and NMR studies have elucidated the three-dimensional structure of S100A1, providing critical insights into its calcium-dependent interactions with regulatory targets in cardiac and skeletal muscle.
How does S100A1 regulate calcium handling in cardiomyocytes?
S100A1 serves as a multifunctional regulator of cardiac calcium cycling through interactions with key calcium handling proteins. In cardiomyocytes, S100A1 directly modulates the activity of both the sarcoplasmic reticulum Ca²⁺-ATPase (SERCA2a) and the ryanodine receptor 2 (RyR2) . During systole, S100A1 enhances calcium-induced calcium release by facilitating RyR2 opening, thereby increasing the amplitude of calcium transients and improving contractile force. During diastole, S100A1 improves SERCA2a activity, accelerating calcium reuptake into the sarcoplasmic reticulum while simultaneously reducing diastolic RyR2 calcium leak . This dual action results in enhanced systolic contractility and improved diastolic relaxation. Studies using S100A1 overexpression models have demonstrated increased calcium transients and enhanced contractile performance in ventricular cardiomyocytes from mice, rats, and rabbits . Importantly, S100A1-mediated inotropy occurs independently of and adds to β-adrenergic receptor stimulation, providing a potential therapeutic advantage without the adverse effects associated with sustained β-adrenergic signaling.
What is the relationship between S100A1 and mitochondrial function in cardiac cells?
S100A1 has been identified in cardiomyocyte mitochondria, where it plays critical roles in energy metabolism. The protein interacts with the mitochondrial F1-ATPase (ATP synthase), enhancing its activity in a dose-dependent manner . This interaction promotes increased ATP production, improving the energetic efficiency of cardiomyocytes. Experimental evidence shows that S100A1ct peptide produces a dose-dependent enhancement of F1-ATP synthase activity, similar to the effects observed with recombinant human S100A1 protein . By simultaneously optimizing calcium cycling and mitochondrial energy production, S100A1 creates a coordinated enhancement of excitation-contraction coupling and bioenergetics in cardiac muscle. This integrated regulatory function is particularly significant in the context of heart failure, where both calcium handling and energy metabolism are compromised. Therapeutic approaches targeting S100A1 may therefore address multiple pathological mechanisms simultaneously, offering advantages over conventional heart failure treatments that typically focus on single pathways.
What evidence supports S100A1 as a therapeutic target for heart failure with reduced ejection fraction (HFrEF)?
Multiple lines of evidence establish S100A1 as a promising therapeutic target for HFrEF. First, S100A1 is significantly downregulated in failing human myocardium, suggesting a mechanistic role in disease progression . Second, genetic studies demonstrate that S100A1 knockout mice experience accelerated heart failure development and increased mortality following myocardial infarction . Conversely, cardiac-specific S100A1 overexpression protects against heart failure development in response to pressure overload and ischemic injury. Third, viral gene transfer of S100A1 in preclinical heart failure models has shown remarkable efficacy in reversing maladaptive remodeling and improving survival . Finally, recent development of S100A1ct peptide therapeutics has demonstrated positive inotropic and antiarrhythmic properties in failing myocardium in vitro and in vivo . Treatment with S100A1ct peptide improves contractile performance and survival in preclinical HFrEF models through mechanisms involving enhanced cardiomyocyte calcium cycling and prevention of β-adrenergic receptor-triggered calcium imbalances . Together, these findings provide compelling evidence that S100A1-based therapies may offer a novel treatment approach for heart failure patients.
How does the S100A1ct peptide compare to full-length S100A1 protein in therapeutic potential?
The S100A1ct peptide represents an innovative therapeutic approach derived from the C-terminal α-helix (helix IV) of the S100A1 protein. Studies show that this peptide can mimic and sometimes exceed the functional effects of the full-length protein . When attached to a cell-penetrating tag, S100A1ct demonstrates several advantages as a potential therapeutic:
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Enhanced cellular uptake: The cell-penetrating properties enable efficient delivery into cardiomyocytes .
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Targeted activity: S100A1ct exhibits dose-dependent enhancement of SERCA2a activity comparable to recombinant human S100A1 .
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Mitochondrial function improvement: Like the parent protein, S100A1ct enhances F1-ATP synthase activity .
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Antiarrhythmic properties: The peptide prevents β-adrenergic receptor-triggered calcium imbalances .
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Pharmacokinetic advantages: As a synthetic peptide, S100A1ct may offer more favorable delivery options compared to gene therapy approaches requiring viral vectors.
Translational research spanning from molecular modeling to large animal cardiac disease models has validated S100A1ct's efficacy, demonstrating improved contractile performance and survival in preclinical HFrEF models following systemic administration . These findings position S100A1ct as a promising lead for peptide-based therapeutics against heart failure with potential for clinical translation.
What analytical methods can differentiate between human and pig S100A1 in preclinical research?
The high homology between human and pig S100A1 proteins (differing by only a single amino acid) presents a significant bioanalytical challenge in preclinical research, particularly for cardiac-directed gene therapy approaches using pig models. An advanced LC-MS/MS approach has been developed to address this challenge . This method can simultaneously quantitate both endogenous (pig) and exogenous (human) S100A1 proteins with high sensitivity and selectivity. The technique exploits the single amino acid difference between species to generate distinct peptide fragments following enzymatic digestion, which are then detected via tandem mass spectrometry . This analytical approach enables:
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Precise quantification of human S100A1 expression following gene therapy
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Measurement of endogenous S100A1 levels in various pig tissues
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Comprehensive evaluation of S100A1 distribution in pig hearts
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Comparative analysis of S100A1 levels between pig and human cardiac samples
This methodology is essential for translational research, as it allows accurate assessment of gene therapy efficacy while controlling for background expression of endogenous protein.
What expression systems are used for producing recombinant human S100A1 protein for research?
Recombinant human S100A1 protein can be produced using several expression systems, with E. coli being the most commonly employed platform for research applications. Commercial sources typically provide E. coli-derived human S100A1 protein comprising the full-length sequence (Met1-Ser94) . The protein is generally supplied in lyophilized form, often reconstituted in PBS with reducing agents such as DTT to maintain proper disulfide bonding .
For research applications requiring carrier-free preparations (without BSA or other carrier proteins), special formulations are available that enhance experimental flexibility, particularly for applications where carrier proteins might interfere with assays or cellular studies . Key considerations for recombinant S100A1 protein production include:
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Purification strategies that maintain protein conformation and activity
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Validation of calcium-binding properties through functional assays
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Storage conditions that preserve protein stability (typically -80°C with avoidance of repeated freeze-thaw cycles)
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Quality control testing for binding to known interaction partners (e.g., HSP70/HSPA1A)
These recombinant proteins serve as valuable tools for in vitro studies examining S100A1 interactions, structure-function relationships, and pharmaceutical development.
What are the key experimental models for studying S100A1 function in cardiovascular research?
Cardiovascular researchers employ a range of experimental models to investigate S100A1 function, each offering distinct advantages:
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Isolated cardiomyocytes: Field-stimulated ventricular cardiomyocytes from mice, rats, and rabbits provide a controlled system for studying S100A1's effects on calcium transients and contractile performance . Voltage-clamped cardiomyocytes allow precise examination of excitation-contraction coupling.
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Transgenic mouse models: S100A1 knockout and cardiac-specific overexpression models have been instrumental in establishing S100A1's in vivo roles. Knockout mice display accelerated heart failure progression and increased mortality after myocardial infarction .
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Viral gene transfer models: AAV9-mediated S100A1 gene delivery has been tested in rodent and large animal heart failure models, demonstrating reversal of maladaptive remodeling and improved survival .
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Large animal models: Pig models of heart failure represent a crucial translational step, as pig cardiac physiology more closely resembles human hearts. S100A1 gene therapy and S100A1ct peptide treatments have shown efficacy in porcine heart failure models .
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Human tissue samples: Analysis of S100A1 expression in human cardiac samples from healthy and failing hearts provides clinically relevant insights and validation of findings from animal models .
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Sarcoplasmic reticulum vesicles: Isolated SR vesicles from S100A1 knockout mice serve as a defined system for examining S100A1's direct effects on SERCA2a activity .
These complementary models enable comprehensive investigation of S100A1 from molecular interactions to therapeutic potential in clinically relevant settings.
What approaches are used for S100A1-based gene therapy in heart failure models?
S100A1-based gene therapy has emerged as a promising approach for treating heart failure, with several key methodological considerations:
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Vector selection: Adeno-associated virus serotype 9 (AAV9) has proven particularly effective for cardiac-targeted gene delivery due to its cardiotropism and safety profile . AAV9-S100A1 constructs have successfully rescued post-ischemic heart failure in preclinical large animal models .
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Delivery routes: Direct intracoronary delivery has been employed to maximize cardiac transduction efficiency while minimizing systemic exposure . This approach enables targeted expression in the myocardium.
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Promoter selection: Cardiac-specific promoters help restrict S100A1 expression to cardiomyocytes, enhancing safety and efficacy by preventing unwanted expression in other tissues.
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Outcome assessment: Comprehensive evaluation of gene therapy effects includes:
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Translational considerations: Large animal studies in porcine models provide critical data on safety, biodistribution, and efficacy prior to human trials. Special analytical methods (LC-MS/MS) enable differentiation between endogenous and therapy-derived S100A1 protein .
Recent investigations have also explored alternative approaches using S100A1-derived peptides (S100A1ct) that may offer similar therapeutic benefits with potentially simplified delivery methods .
Product Science Overview
S100 Calcium Binding Protein A1, also known as S100A1, is a member of the S100 family of proteins. These proteins are characterized by their ability to bind calcium ions through EF-hand motifs, which are helix-loop-helix structural domains . S100A1 is highly expressed in cardiac and skeletal muscle tissues, as well as in the brain .
S100A1 contains four EF-hand calcium-binding motifs in its dimerized form . It can exist as either a heterodimer or a homodimer, with the homodimer being formed through hydrophobic interactions between specific helices . The protein’s structure allows it to undergo conformational changes upon binding calcium ions, which is crucial for its function .
S100A1 plays a significant role in various biological processes, including calcium homeostasis, chondrocyte biology, and cardiomyocyte regulation . In cardiomyocytes, S100A1 regulates a network controlling sarcoplasmic reticulum calcium cycling and mitochondrial function . It interacts with several key proteins, such as ryanodine receptors, sarcoplasmic reticulum calcium-ATPase, and mitochondrial F1-ATPase .
The expression of S100A1 has been implicated in several diseases. Reduced expression of this protein is associated with cardiomyopathies, which are diseases of the heart muscle that can lead to heart failure . Additionally, S100A1 has shown promise as a candidate for gene therapy to treat post-myocardial infarction cardiac tissue .
