GO:1903243 negative regulation of cardiac muscle hypertrophy in response to stress: Signaling Brakes, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1903243 describes any biological process that stops, prevents, or reduces the extent of cardiac muscle hypertrophy triggered by stress.
• Pathological cardiac hypertrophy is a maladaptive response to pressure overload, neurohormonal activation, or ischemic injury, and its negative regulation is a major therapeutic goal.
• Key molecular brakes include USP28, MCU-CaMKIIδB signaling, PRMT7-JAK/STAT-SOCS3, GADD45A, and circadian regulators such as CLOCK/BMAL1.
• Calcium handling, mitochondrial calcium uptake, and redox balance are central nodes where negative regulation is exerted.
• Loss of negative regulators such as GADD45A or PRMT7 exacerbates inflammation, fibrosis, and hypertrophy in preclinical models.
• CRISPR knockout, point-mutation, knock-in, and overexpression models are essential to dissect causal roles of these regulators in cardiomyocytes.
Description
Cardiac muscle hypertrophy in response to stress is an adaptive growth response that initially normalizes wall stress but frequently progresses to heart failure. The Gene Ontology term GO:1903243, negative regulation of cardiac muscle hypertrophy in response to stress, captures the endogenous processes that restrain this maladaptive growth. Understanding these brakes is critical because their failure or suppression accelerates pathological remodeling, whereas their enhancement may be cardioprotective. Recent studies have identified diverse negative regulators, including the deubiquitinase USP28, the mitochondrial calcium uniporter (MCU) via CaMKIIδB, the arginine methyltransferase PRMT7, and the stress-response protein GADD45A. These discoveries position GO:1903243 as a hub for mechanistic and translational research in cardiac hypertrophy and heart failure.
negative regulation of cardiac muscle hypertrophy in response to stress At A Glance
| GO ID | GO:1903243 |
|---|---|
| GO term | negative regulation of cardiac muscle hypertrophy in response to stress |
| Ontology | biological_process |
| Synonym | down regulation of cardiac muscle hypertrophy in response to stress; down-regulation of cardiac muscle hypertrophy in response to stress; downregulation of cardiac muscle hypertrophy in response to stress; inhibition of cardiac muscle hypertrophy in response to stress |
| Major function | Restraining stress-induced cardiomyocyte growth and pathological remodeling |
| Key regulators | USP28, MCU/CaMKIIδB, PRMT7, GADD45A, circadian clock components |
| Associated diseases | Heart failure, hypertrophic cardiomyopathy, postmenopausal cardiomyopathy |
| Research models | Transverse aortic constriction, isoproterenol infusion, CRISPR knockout and overexpression in cardiomyocytes |
What Is GO:1903243?
GO:1903243 is defined as any process that stops, prevents, or reduces the frequency, rate, or extent of cardiac muscle hypertrophy in response to stress. It is a biological_process term that encompasses molecular, cellular, and systemic mechanisms that limit stress-induced cardiomyocyte enlargement. This term is distinct from general negative regulation of cell growth because it specifically refers to hypertrophy triggered by stress, such as pressure overload or neurohormonal stimulation.
Why Is negative regulation of cardiac muscle hypertrophy in response to stress Important in Cell Biology?
GO:1903243 is important because pathological cardiac hypertrophy is a leading precursor to heart failure, arrhythmias, and sudden cardiac death. Identifying and characterizing negative regulators offers potential therapeutic targets to halt or reverse maladaptive remodeling. Moreover, the term provides a structured framework for annotating gene functions in cardiac stress responses, enabling systematic discovery of cardioprotective pathways.
• Pathological hypertrophy is a major risk factor for heart failure and arrhythmias.
• Negative regulators such as USP28 and GADD45A are causally linked to hypertrophy suppression in preclinical models.
• MCU-CaMKIIδB signaling limits pathological remodeling by modulating mitochondrial calcium.
• PRMT7 regulates JAK/STAT/SOCS3 signaling and protects against postmenopausal cardiomyopathy.
• Circadian governance of cardiac growth influences hypertrophic responses.
• Calcium and stretch-sensing mechanisms are central to hypertrophy regulation.
• The term aids in functional annotation of cardiac transcriptomic and proteomic data.
• CRISPR-based models enable precise interrogation of candidate negative regulators.
• Therapeutic targeting of negative regulators may complement existing heart failure therapies.
• Understanding negative regulation can inform biomarker discovery for early remodeling.
What Happens During negative regulation of cardiac muscle hypertrophy in response to stress?
Stress sensing and initiation of hypertrophic signaling
In simple terms: The heart senses stress such as high blood pressure and starts a growth program.
Mechanical stretch, neurohormonal activation, and ischemic injury trigger intracellular signaling cascades that initiate cardiac hypertrophy. Calcium influx and stretch-sensitive channels are early sensors that activate calcineurin-NFAT, MAPK, and PI3K-Akt pathways. These events set the stage for negative regulation by endogenous brakes.
Calcium handling and mitochondrial calcium uptake
In simple terms: Calcium levels inside heart cells are tightly controlled to prevent excessive growth.
The mitochondrial calcium uniporter (MCU) and CaMKIIδB modulate mitochondrial calcium and limit pathological remodeling. Elevated MCU expression by CaMKIIδB reduces hypertrophic signaling and preserves cardiac function in pressure overload models. Calcium-dependent signaling is therefore a key node for negative regulation.
Protein quality control and deubiquitination
In simple terms: Cells remove or stabilize proteins to keep growth signals in check.
USP28, a deubiquitinase, negatively regulates antioxidant response and promotes hypertrophy by deubiquitinating TRIM21, thereby acting as a brake on protective pathways. This illustrates how ubiquitin-proteasome dynamics control the balance between adaptive and maladaptive growth.
Epigenetic and post-translational regulation
In simple terms: Chemical marks on DNA and proteins can turn growth genes on or off.
PRMT7, an arginine methyltransferase, regulates JAK/STAT/SOCS3 signaling and suppresses postmenopausal cardiomyopathy. GADD45A suppression promotes inflammation, fibrosis, and hypertrophy, indicating that stress-response proteins act as negative regulators. These epigenetic and post-translational mechanisms fine-tune hypertrophic responses.
Circadian and systemic modulation
In simple terms: The body clock influences how the heart grows under stress.
Circadian governance of cardiac growth involves clock components that modulate hypertrophic gene programs. Disruption of circadian rhythms exacerbates maladaptive remodeling, highlighting systemic control of negative regulation.
Key Genes Involved in GO:1903243 negative regulation of cardiac muscle hypertrophy in response to stress
The following genes and proteins have been experimentally linked to negative regulation of cardiac muscle hypertrophy in response to stress.
| Gene | Major Role | Research Relevance |
|---|---|---|
| USP28 | Deubiquitinase that negatively regulates antioxidant response and promotes hypertrophy via TRIM21 | Target for modulating oxidative stress in hypertrophy |
| MCU | Mitochondrial calcium uniporter; elevated expression by CaMKIIδB limits remodeling | Regulates mitochondrial calcium and hypertrophic signaling |
| CAMK2D | CaMKIIδB isoform that upregulates MCU and limits pathological remodeling | Key kinase in calcium-dependent negative regulation |
| PRMT7 | Arginine methyltransferase regulating JAK/STAT/SOCS3 | Protects against postmenopausal cardiomyopathy |
| GADD45A | Stress-response protein; suppression promotes inflammation and hypertrophy | Negative regulator of cardiac remodeling |
| SOCS3 | Suppressor of cytokine signaling downstream of PRMT7 | Modulates JAK/STAT-driven hypertrophy |
| TRIM21 | E3 ubiquitin ligase deubiquitinated by USP28 | Links ubiquitination to antioxidant response |
| CLOCK | Circadian clock transcription factor | Modulates cardiac growth rhythms |
| BMAL1 | Circadian clock partner of CLOCK | Influences hypertrophic gene expression |
| NFAT | Calcineurin-dependent transcription factor | Central to hypertrophic gene program |
| MAPK1 | Mitogen-activated protein kinase | Stress-activated hypertrophic signaling |
| AKT1 | PI3K-Akt pathway kinase | Regulates physiological and pathological growth |
| SIRT3 | Mitochondrial deacetylase | Linked to mitochondrial function in muscle aging |
| PGC1A | Mitochondrial biogenesis regulator | Downstream of SIRT3 in muscle |
| HSF1 | Heat shock transcription factor | Regulates proteostasis in muscle |
| CALM1 | Calmodulin; calcium sensor | Mediates calcium-dependent signaling |
| JAK2 | Janus kinase upstream of STAT | Cytokine signaling in hypertrophy |
How Is negative regulation of cardiac muscle hypertrophy in response to stress Regulated?
Negative regulation of cardiac muscle hypertrophy is controlled by interconnected signaling modules, including calcium-CaMKII-MCU, JAK/STAT/SOCS3, ubiquitin-proteasome, and circadian pathways. These pathways respond to stress intensity and duration, and their dysregulation shifts the balance toward maladaptive growth.
negative regulation of cardiac muscle hypertrophy in response to stress and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| USP28 | Cardiac hypertrophy via antioxidant response suppression | Cardiomyocyte-specific knockout and overexpression |
| MCU | Pathological remodeling under pressure overload | Transverse aortic constriction in MCU transgenic mice |
| PRMT7 | Postmenopausal cardiomyopathy | PRMT7 knockout mice with ovariectomy |
| GADD45A | Cardiac remodeling with inflammation and fibrosis | GADD45A knockout and rescue in pressure overload |
| CLOCK/BMAL1 | Circadian disruption and hypertrophy | Clock mutant mice and cardiomyocyte-specific deletion |
Heart failure and pathological remodeling
Loss of negative regulators such as GADD45A or PRMT7 accelerates inflammation, fibrosis, and hypertrophy, contributing to heart failure progression. Enhancing these brakes may slow remodeling.
Postmenopausal cardiomyopathy
PRMT7 regulates JAK/STAT/SOCS3 signaling, and its dysfunction is linked to postmenopausal cardiomyopathy. This highlights sex-specific aspects of negative regulation.
Hypertrophic cardiomyopathy and arrhythmias
Pathological hypertrophy is a substrate for arrhythmias and sudden cardiac death. Negative regulators that limit cardiomyocyte growth may reduce arrhythmic risk.
From negative regulation of cardiac muscle hypertrophy in response to stress-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of a candidate gene exacerbate hypertrophy? | CRISPR knockout in cardiomyocytes or mouse models |
| Does a point mutation in a regulator alter its function? | CRISPR point-mutation knock-in in iPSC-derived cardiomyocytes |
| Does overexpression of a negative regulator protect against stress? | AAV-mediated overexpression in mouse heart |
| Does a tagged version of the protein reveal interactors? | CRISPR knock-in of epitope tag |
| Does a regulator affect mitochondrial calcium? | MCU knockout and CaMKIIδB overexpression |
| Does circadian disruption modify hypertrophy? | Clock/BMAL1 knockout mice |
How to Study the negative regulation of cardiac muscle hypertrophy in response to stress Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Transcriptome changes | Identify hypertrophy-associated gene programs |
| Proteomics | Protein abundance and modifications | Discover regulators and post-translational changes |
| Echocardiography | Cardiac structure and function | Assess hypertrophy in TAC models |
| Histology | Cardiomyocyte size and fibrosis | Quantify remodeling |
| Calcium imaging | Mitochondrial and cytosolic calcium | Evaluate MCU/CaMKII effects |
| Luciferase reporter assays | Transcriptional activity | Measure NFAT or JAK/STAT activity |
| CRISPR screening | Gene function at scale | Identify novel negative regulators |
| Co-immunoprecipitation | Protein interactions | Map USP28-TRIM21 or PRMT7 complexes |
Transcriptomic and proteomic profiling
RNA-seq and proteomics can identify genes and proteins whose expression changes during negative regulation of hypertrophy. These methods reveal pathways such as JAK/STAT and antioxidant response.
Functional assays in cardiomyocytes
Primary cardiomyocytes or iPSC-derived cardiomyocytes can be subjected to stretch or neurohormonal stimulation to measure hypertrophy markers such as ANP and BNP. CRISPR perturbations allow causal testing.
In vivo pressure overload models
Transverse aortic constriction (TAC) and isoproterenol infusion are standard models to assess negative regulation in vivo. Echocardiography and histology quantify hypertrophy and fibrosis.
Calcium and mitochondrial imaging
Live-cell imaging of mitochondrial calcium and ROS can reveal how regulators such as MCU and USP28 affect hypertrophic signaling. These approaches link molecular mechanisms to cellular outcomes.
How CRISPR Can Be Used to Study GO:1903243 negative regulation of cardiac muscle hypertrophy in response to stress
Knockout
CRISPR knockout of candidate negative regulators such as USP28, PRMT7, or GADD45A in cardiomyocytes or mice can reveal whether their loss exacerbates stress-induced hypertrophy. This approach provides causal evidence for GO:1903243 annotations.
Point Mutation
Point mutations in catalytic residues of enzymes like USP28 or PRMT7 can dissect enzymatic versus scaffolding functions in negative regulation. CRISPR point-mutation knock-in enables precise structure-function studies.
Knock-in
Knock-in of epitope tags or fluorescent reporters at endogenous loci allows visualization and interactome analysis of negative regulators under stress. This preserves physiological expression levels.
Overexpression
Overexpression of negative regulators such as MCU or GADD45A via AAV or transgenic models can test cardioprotective effects against pressure overload. This complements loss-of-function studies.
How EDITGENE Supports negative regulation of cardiac muscle hypertrophy in response to stress Research
Researchers studying negative regulation of cardiac muscle hypertrophy in response to stress-related genes often need to determine whether a candidate gene is causally involved in restraining pathological growth. EDITGENE provides end-to-end CRISPR services to generate precisely engineered cell and animal models for such investigations.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of cardiac muscle hypertrophy in response to stress research.
Frequently Asked Questions About negative regulation of cardiac muscle hypertrophy in response to stress
What is GO:1903243?
GO:1903243 is the Gene Ontology term for negative regulation of cardiac muscle hypertrophy in response to stress, describing any process that stops, prevents, or reduces stress-induced cardiomyocyte growth.
What genes are involved in negative regulation of cardiac muscle hypertrophy in response to stress?
Key genes include USP28, MCU, CAMK2D, PRMT7, GADD45A, SOCS3, TRIM21, and circadian clock genes such as CLOCK and BMAL1.
How does USP28 regulate cardiac hypertrophy?
USP28 negatively regulates antioxidant response and promotes hypertrophy by deubiquitinating TRIM21, thereby acting as a brake on protective pathways.
What is the role of MCU in pathological cardiac remodeling?
Elevated MCU expression by CaMKIIδB limits pathological cardiac remodeling by modulating mitochondrial calcium.
How does PRMT7 protect against postmenopausal cardiomyopathy?
PRMT7 regulates JAK/STAT/SOCS3 signaling, and its dysfunction is linked to postmenopausal cardiomyopathy.
What is the function of GADD45A in cardiac remodeling?
GADD45A suppression promotes inflammation, fibrosis, and hypertrophy, indicating it acts as a negative regulator of remodeling.
How is calcium involved in cardiac hypertrophy?
Calcium influx and stretch-sensitive channels activate hypertrophic signaling, and calcium handling is a key node for negative regulation.
What models are used to study negative regulation of cardiac hypertrophy?
Transverse aortic constriction, isoproterenol infusion, and CRISPR-engineered cardiomyocytes are commonly used.
Can CRISPR screens identify new negative regulators of cardiac hypertrophy?
Yes, genome-wide CRISPR screens can uncover novel genes that restrain stress-induced hypertrophy.
What diseases are linked to GO:1903243?
Heart failure, hypertrophic cardiomyopathy, postmenopausal cardiomyopathy, and arrhythmias are linked to dysregulated negative regulation.
Conclusion
GO:1903243 provides a precise ontological framework for studying endogenous brakes on stress-induced cardiac hypertrophy. Experimental evidence implicates diverse regulators such as USP28, MCU-CaMKIIδB, PRMT7, GADD45A, and circadian components in limiting maladaptive growth. Leveraging CRISPR models and multi-omics approaches will accelerate the translation of these insights into therapies for heart failure.
References
- 1. Nakamura M et al.. 2018. Mechanisms of physiological and pathological cardiac hypertrophy.. Nat Rev Cardiol 15(7):387-407 PMID: 29674714
- 2. Han J et al.. 2024. Cardiomyocyte-derived USP28 negatively regulates antioxidant response and promotes cardiac hypertrophy via deubiquitinating TRIM21.. Theranostics 14(16):6236-6248 PMID: 39431010
- 3. Wang P et al.. 2022. Elevated MCU Expression by CaMKIIδB Limits Pathological Cardiac Remodeling.. Circulation 145(14):1067-1083 PMID: 35167328
- 4. Zhang J et al.. 2026. Skeletal Muscle HSF1 Alleviates Age-Associated Sarcopenia and Mitochondrial Function Decline via SIRT3-PGC1α Axis.. Adv Sci (Weinh) 13(11):e10368 PMID: 41400028
- 5. Latimer MN et al.. 2022. Circadian Governance of Cardiac Growth.. Cells 11(9) PMID: 35563800
- 6. Calaghan SC et al.. 1999. The role of calcium in the response of cardiac muscle to stretch.. Prog Biophys Mol Biol 71(1):59-90 PMID: 10070212
- 7. Ahn BY et al.. 2024. Prmt7 regulates the JAK/STAT/Socs3 signaling pathway in postmenopausal cardiomyopathy.. Exp Mol Med 56(3):711-720 PMID: 38486105
- 8. Rostami A et al.. 2025. GADD45A suppression contributes to cardiac remodeling by promoting inflammation, fibrosis and hypertrophy.. Cell Mol Life Sci 82(1):189 PMID: 40301189
