GO:1903242 regulation of cardiac muscle hypertrophy in response to stress: Signaling Mechanisms, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1903242 describes any process that modulates the frequency, rate or extent of cardiac muscle hypertrophy in response to stress, encompassing both physiological (adaptive) and pathological (maladaptive) growth of cardiomyocytes.
• Pathological cardiac hypertrophy is driven by neurohormonal and mechanical stress signals that converge on calcium-dependent signaling, kinase cascades, and transcriptional reprogramming [1,7].
• Metabolic rewiring, including shifts in substrate utilization and mitochondrial function, is a hallmark of hypertrophic remodeling and is mechanistically coupled to the regulation of hypertrophy [2,4].
• E3 ubiquitin ligases such as TRIM16, USP28, NEDD4, and TRIM21 act as key regulators of cardiac hypertrophy by controlling protein stability and antioxidant responses [3,5,6].
• Yap1 and CaMKIIδB are stress-responsive regulators that link mechanical overload and calcium signaling to mitochondrial biogenesis and pathological remodeling [7,8].
• CRISPR-based knockout, knock-in, point-mutation, and overexpression models are essential tools for dissecting causal roles of specific genes in the regulation of cardiac hypertrophy [1,3,6].
Description
Cardiac hypertrophy is an adaptive response of the heart to increased workload or stress, but when sustained it becomes maladaptive and predisposes to heart failure. The Gene Ontology term GO:1903242, regulation of cardiac muscle hypertrophy in response to stress, captures the regulatory processes that control the frequency, rate, or extent of this hypertrophic growth specifically under stress conditions. This term is critical for researchers because it provides a framework to annotate and interrogate the molecular mechanisms that either promote or suppress pathological cardiac remodeling [1,2]. Understanding these regulatory mechanisms is essential for identifying therapeutic targets that can preserve adaptive hypertrophy while preventing the transition to heart failure [2,4]. Recent studies have uncovered diverse regulators, including E3 ubiquitin ligases, metabolic sensors, and calcium-dependent kinases, that modulate hypertrophic signaling in cardiomyocytes [3,5,6,7,8]. These findings highlight the complexity of the regulatory network and the need for precise genetic models to dissect causal relationships [1,6].
regulation of cardiac muscle hypertrophy in response to stress At A Glance
| GO ID | GO:1903242 |
|---|---|
| GO term | regulation of cardiac muscle hypertrophy in response to stress |
| Ontology | biological_process |
| Synonym | none |
| Major function | Modulates the frequency, rate or extent of cardiac muscle hypertrophy under stress conditions |
| Related processes | Cardiac muscle hypertrophy, stress response, pathological cardiac remodeling |
| Key regulators | E3 ubiquitin ligases, calcium/calmodulin-dependent kinases, metabolic sensors, transcription factors |
| Disease relevance | Heart failure, hypertrophic cardiomyopathy, ischemic heart disease |
What Is GO:1903242?
GO:1903242 is defined as any process that modulates the frequency, rate or extent of cardiac muscle hypertrophy in response to stress. In other words, it encompasses all molecular and cellular events that either enhance or suppress the hypertrophic growth of cardiac muscle cells when the heart is exposed to stressors such as pressure overload, neurohormonal stimulation, or metabolic stress.
Why Is regulation of cardiac muscle hypertrophy in response to stress Important in Cell Biology?
The regulation of cardiac muscle hypertrophy in response to stress is a central determinant of cardiac outcomes in hypertension, valvular disease, and myocardial infarction. While short-term hypertrophy can be compensatory, sustained pathological hypertrophy leads to ventricular dilation, contractile dysfunction, and heart failure [1,2]. Therefore, understanding the molecular regulators of this process is critical for developing therapies that prevent or reverse maladaptive remodeling [2,4].
• Pathological cardiac hypertrophy is an independent risk factor for heart failure and sudden cardiac death.
• The process integrates mechanical, neurohormonal, and metabolic stress signals [1,2].
• E3 ubiquitin ligases and deubiquitinases dynamically regulate hypertrophic signaling proteins [3,5,6].
• Calcium-dependent kinases such as CaMKIIδB modulate mitochondrial function and hypertrophy.
• Yap1 links mechanical stress to mitochondrial biogenesis and cardiomyocyte growth.
• Metabolic interventions, such as semaglutide, can ameliorate cardiac remodeling by optimizing substrate utilization.
• Identifying suppressors of pathological hypertrophy may reveal new therapeutic targets.
• CRISPR screening enables unbiased discovery of regulators of cardiomyocyte hypertrophy.
• Human induced pluripotent stem cell-derived cardiomyocytes provide a platform for studying hypertrophy regulation.
• Animal models of pressure overload (TAC) are standard for studying GO:1903242 in vivo [5,8].
What Happens During regulation of cardiac muscle hypertrophy in response to stress?
Stress Sensing and Initiation of Hypertrophic Signaling
In simple terms: The heart senses stress and starts a growth signal.
Cardiomyocytes detect mechanical stretch, neurohormonal stimuli (e.g., angiotensin II, endothelin-1), and metabolic stress through membrane receptors and mechanosensors. This triggers intracellular signaling cascades, including calcium/calmodulin-dependent kinase II (CaMKII) and mitogen-activated protein kinase (MAPK) pathways, which initiate transcriptional reprogramming [1,7]. The initial response aims to compensate for increased workload by enhancing contractility and promoting cell growth.
Transcriptional and Epigenetic Reprogramming
In simple terms: The cell switches on a fetal gene program to grow.
Stress signals activate transcription factors such as GATA4, MEF2, and NFAT, leading to re-expression of fetal genes (e.g., NPPA, NPPB, MYH7) and repression of adult genes (e.g., MYH6). Epigenetic modifications, including histone acetylation and DNA methylation, further shape the hypertrophic transcriptome. This reprogramming supports increased protein synthesis and sarcomeric assembly.
Metabolic Rewiring and Mitochondrial Adaptation
In simple terms: The heart changes how it makes energy to support growth.
Hypertrophic cardiomyocytes shift substrate utilization from fatty acid oxidation to glucose oxidation, accompanied by mitochondrial dysfunction and increased reactive oxygen species (ROS). Regulators such as Creb5 and NR4a1 modulate this metabolic switch, and interventions like semaglutide can restore metabolic balance and attenuate remodeling. Mitochondrial biogenesis, controlled by Yap1 and CaMKIIδB, is critical for matching energy supply to demand [7,8].
Protein Quality Control and Ubiquitin-Proteasome System
In simple terms: The cell decides which proteins to keep or destroy to control growth.
E3 ubiquitin ligases and deubiquitinases regulate the stability of key hypertrophic effectors. TRIM16 suppresses pathological hypertrophy by targeting specific proteins for degradation, while USP28 deubiquitinates TRIM21 to promote antioxidant response and hypertrophy. NEDD4-mediated degradation of GSNOR aggravates hypertrophy and dysfunction. This dynamic balance determines whether hypertrophy remains adaptive or becomes maladaptive [3,5,6].
Resolution or Progression to Heart Failure
In simple terms: The growth either stops safely or continues to heart failure.
If the stress is resolved, hypertrophy may regress; however, sustained stress leads to maladaptive remodeling, fibrosis, and contractile dysfunction. The transition involves continued activation of pro-hypertrophic signaling, increased apoptosis, and metabolic collapse. Understanding the regulatory checkpoints that determine this transition is a major goal of cardiovascular research [1,2].
Key Genes Involved in GO:1903242 regulation of cardiac muscle hypertrophy in response to stress
The following genes and proteins have been experimentally implicated in the regulation of cardiac muscle hypertrophy in response to stress.
| Gene | Major Role | Research Relevance |
|---|---|---|
| TRIM16 | E3 ubiquitin ligase that suppresses pathological cardiac hypertrophy | Potential therapeutic target; KO exacerbates hypertrophy |
| USP28 | Deubiquitinase that negatively regulates antioxidant response and promotes hypertrophy | KO attenuates hypertrophy; links to TRIM21 |
| NEDD4 | E3 ligase that degrades GSNOR, aggravating hypertrophy | Inhibition may be protective |
| TRIM21 | Target of USP28; involved in antioxidant response | Modulates redox balance in hypertrophy |
| GSNOR | S-nitrosoglutathione reductase; degraded by NEDD4 | Its degradation worsens hypertrophy |
| CaMKIIδB | Calcium/calmodulin-dependent kinase; limits pathological remodeling | Elevated expression protects mitochondria |
| Yap1 | Transcriptional co-activator; modulates mitochondrial biogenesis | Mechanical stress sensor; KO impairs adaptation |
| Creb5 | Transcription factor regulating energy substrate utilization | Target of semaglutide; modulates remodeling |
| NR4a1 | Nuclear receptor involved in metabolic regulation | Part of Creb5/NR4a1 axis |
| GATA4 | Transcription factor driving fetal gene program | Central to hypertrophic gene expression |
| MEF2 | Transcription factor activated by stress signaling | Regulates sarcomeric genes |
| NFAT | Calcineurin-dependent transcription factor | Promotes hypertrophic growth |
| MYH7 | Beta-myosin heavy chain; fetal isoform | Re-expressed in hypertrophy |
| NPPA | Atrial natriuretic peptide; fetal gene | Biomarker of hypertrophy |
| NPPB | B-type natriuretic peptide; fetal gene | Clinical biomarker of heart failure |
| mTOR | Kinase integrating growth signals | Central regulator of protein synthesis |
| AMPK | Energy sensor; inhibits mTOR | Modulates metabolic stress response |
How Is regulation of cardiac muscle hypertrophy in response to stress Regulated?
The regulation of cardiac muscle hypertrophy in response to stress is controlled by a multilayered network. Upstream, neurohormonal and mechanical signals activate G-protein coupled receptors and integrins, leading to calcium influx and activation of CaMKII, calcineurin/NFAT, and MAPK pathways. Metabolic sensors such as AMPK and mTOR integrate energy status with growth signals; AMPK inhibits mTOR to limit hypertrophy under low-energy conditions, while mTOR promotes protein synthesis when nutrients are available. E3 ubiquitin ligases (TRIM16, NEDD4) and deubiquitinases (USP28) provide post-translational control by targeting key signaling proteins for degradation or stabilization [3,5,6]. Transcription factors such as Yap1 and Creb5 link mechanical and metabolic stress to mitochondrial biogenesis and substrate utilization [4,8]. This regulatory network ensures that hypertrophy is tightly coupled to stress intensity and duration [1,2].
regulation of cardiac muscle hypertrophy in response to stress and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| TRIM16 | Heart failure; loss exacerbates hypertrophy | Cardiomyocyte-specific KO mice |
| USP28 | Hypertrophy; promotes antioxidant response | KO mice; TAC model |
| NEDD4 | Cardiac dysfunction; degrades GSNOR | Overexpression and KO mice |
| Yap1 | Mechanical stress-induced hypertrophy | Cardiomyocyte-specific KO |
| CaMKIIδB | Pathological remodeling; mitochondrial dysfunction | Transgenic overexpression |
Heart Failure
Sustained pathological cardiac hypertrophy is a major precursor to heart failure. Dysregulation of GO:1903242 processes, such as excessive activation of pro-hypertrophic signaling or failure of endogenous suppressors like TRIM16, leads to ventricular dilation and contractile dysfunction [1,6]. Metabolic remodeling and mitochondrial dysfunction further exacerbate disease progression [2,4].
Hypertrophic Cardiomyopathy
Mutations in sarcomeric genes can cause hypertrophic cardiomyopathy, a disease characterized by inappropriate cardiac hypertrophy. The regulatory mechanisms under GO:1903242, including calcium handling and transcriptional reprogramming, are central to the pathogenesis of this condition.
Ischemic Heart Disease
Following myocardial infarction, the surviving myocardium undergoes compensatory hypertrophy to maintain cardiac output. However, maladaptive regulation of this response can lead to adverse remodeling and heart failure. Regulators such as Yap1 and CaMKIIδB modulate the hypertrophic response to ischemic stress [7,8].
From regulation of cardiac muscle hypertrophy in response to stress-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X suppress pathological hypertrophy? | Cardiomyocyte-specific knockout (KO) mice subjected to TAC |
| Does a point mutation in gene X alter its function in hypertrophy? | Knock-in mice expressing mutant gene X |
| Does overexpression of gene X protect against hypertrophy? | Transgenic overexpression mice |
| Where is protein X localized during hypertrophy? | Tagged knock-in (e.g., GFP) mice |
| Does gene X regulate metabolic reprogramming? | Inducible KO mice with metabolomic profiling |
| Can CRISPR activation of gene X prevent hypertrophy? | CRISPRa in human iPSC-derived cardiomyocytes |
How to Study the regulation of cardiac muscle hypertrophy in response to stress Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Global gene expression changes | Identify fetal gene program and novel regulators |
| Proteomics | Protein abundance and modifications | Discover E3 ligase substrates |
| Ubiquitinome profiling | Ubiquitination sites and dynamics | Map ubiquitin-proteasome regulation |
| Confocal imaging | Cardiomyocyte size and sarcomere structure | Quantify hypertrophy in vitro |
| Calcium transient assay | Calcium handling and signaling | Assess CaMKII pathway activity |
| CRISPR screen | Gene function at scale | Unbiased discovery of hypertrophy regulators |
| Metabolomics | Substrate utilization and metabolite levels | Study metabolic rewiring [2,4] |
| Echocardiography | Cardiac function and wall thickness | In vivo assessment of hypertrophy [5,8] |
Transcriptomic Profiling (RNA-seq)
RNA sequencing of hypertrophic hearts or cardiomyocytes identifies global changes in gene expression, including fetal gene re-expression and pathway activation. This method is widely used to discover novel regulators within GO:1903242 [1,4].
Proteomics and Ubiquitinome Analysis
Mass spectrometry-based proteomics can quantify protein abundance and post-translational modifications, such as ubiquitination, to identify substrates of E3 ligases involved in hypertrophy regulation [3,5,6].
Imaging and Functional Assays
Confocal imaging of cardiomyocyte size, sarcomere organization, and mitochondrial morphology provides direct readouts of hypertrophy. Functional assays such as calcium transient measurements and contractility analysis assess the physiological impact of regulatory genes [7,8].
CRISPR Library Screening
Genome-wide CRISPR knockout or activation screens in cardiomyocytes under hypertrophic stimuli (e.g., phenylephrine) enable unbiased discovery of regulators of GO:1903242. Hits are validated in vivo using animal models.
How CRISPR Can Be Used to Study GO:1903242 regulation of cardiac muscle hypertrophy in response to stress
Knockout
CRISPR knockout of candidate genes in cardiomyocytes or mice is used to determine loss-of-function effects on hypertrophy. For example, knockout of TRIM16 exacerbates pathological hypertrophy, confirming its suppressive role. Knockout of USP28 attenuates hypertrophy, demonstrating its pro-hypertrophic function.
Point Mutation
CRISPR-mediated point mutations can mimic human disease variants or disrupt specific phosphorylation sites. This approach helps dissect the contribution of individual amino acids to the regulation of cardiac hypertrophy.
Knock-in
Knock-in of reporter tags (e.g., GFP) or human disease alleles allows tracking of protein localization and function in vivo. Tagged knock-in models are valuable for studying dynamic regulation of hypertrophy-related proteins.
Overexpression
CRISPR activation (CRISPRa) or transgenic overexpression enables gain-of-function studies. Overexpression of CaMKIIδB limits pathological remodeling, while overexpression of NEDD4 aggravates hypertrophy [5,7].
How EDITGENE Supports regulation of cardiac muscle hypertrophy in response to stress Research
Researchers studying regulation of cardiac muscle hypertrophy in response to stress-related genes often need to determine whether a candidate gene is causally involved in the hypertrophic response. EDITGENE provides a comprehensive suite of CRISPR-based services to accelerate this discovery process, from knockout to overexpression and library screening.
Contact EDITGENE today to design your custom CRISPR model for regulation of cardiac muscle hypertrophy in response to stress research.
Frequently Asked Questions About regulation of cardiac muscle hypertrophy in response to stress
What is GO:1903242?
GO:1903242 is a Gene Ontology term for regulation of cardiac muscle hypertrophy in response to stress, defined as any process that modulates the frequency, rate or extent of cardiac muscle hypertrophy under stress conditions.
What genes are involved in regulation of cardiac muscle hypertrophy in response to stress?
Key genes include TRIM16, USP28, NEDD4, TRIM21, GSNOR, CaMKIIδB, Yap1, Creb5, and NR4a1, among others [3,4,5,6,7,8].
How is cardiac muscle hypertrophy regulated under stress?
It is regulated by a network of calcium-dependent kinases, E3 ubiquitin ligases, metabolic sensors, and transcription factors that integrate stress signals into growth responses [1,2].
What is the difference between physiological and pathological cardiac hypertrophy?
Physiological hypertrophy is adaptive and reversible, while pathological hypertrophy is maladaptive, sustained, and leads to heart failure; both are regulated by distinct signaling pathways [1,2].
Which E3 ubiquitin ligases regulate cardiac hypertrophy?
TRIM16 suppresses pathological hypertrophy, NEDD4 aggravates it by degrading GSNOR, and USP28 promotes hypertrophy via TRIM21 deubiquitination [3,5,6].
How does CaMKIIδB affect cardiac remodeling?
Elevated CaMKIIδB limits pathological remodeling by preserving mitochondrial function and reducing oxidative stress.
What role does Yap1 play in cardiac hypertrophy?
Yap1 modulates cardiomyocyte hypertrophy via impaired mitochondrial biogenesis in response to chronic mechanical stress overload.
Can metabolic interventions regulate cardiac hypertrophy?
Yes, semaglutide ameliorates cardiac remodeling by optimizing energy substrate utilization through the Creb5/NR4a1 axis.
What models are used to study GO:1903242?
Common models include transverse aortic constriction (TAC) in mice, cardiomyocyte-specific knockout/transgenic mice, and human iPSC-derived cardiomyocytes [1,5,8].
How can CRISPR help study regulation of cardiac muscle hypertrophy?
CRISPR knockout, knock-in, point mutation, and overexpression enable causal testing of candidate genes in hypertrophy regulation [1,3,6].
Conclusion
GO:1903242 encompasses the complex regulatory mechanisms that control cardiac muscle hypertrophy in response to stress. Dysregulation of these processes is central to the pathogenesis of heart failure and other cardiac diseases. Recent research has identified diverse regulators, including E3 ubiquitin ligases, metabolic sensors, and calcium-dependent kinases, that offer potential therapeutic targets. CRISPR-based models are indispensable for dissecting these mechanisms and translating findings into clinical applications.
References
- 1. Nakamura M et al.. 2018. Mechanisms of physiological and pathological cardiac hypertrophy.. Nat Rev Cardiol 15(7):387-407 PMID: 29674714
- 2. Ritterhoff J et al.. 2023. Metabolic mechanisms in physiological and pathological cardiac hypertrophy: new paradigms and challenges.. Nat Rev Cardiol 20(12):812-829 PMID: 37237146
- 3. 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
- 4. Ma YL et al.. 2024. Semaglutide ameliorates cardiac remodeling in male mice by optimizing energy substrate utilization through the Creb5/NR4a1 axis.. Nat Commun 15(1):4757 PMID: 38834564
- 5. Tang X et al.. 2025. NEDD4-Mediated GSNOR Degradation Aggravates Cardiac Hypertrophy and Dysfunction.. Circ Res 136(4):422-438 PMID: 39846173
- 6. Liu J et al.. 2022. The E3 Ligase TRIM16 Is a Key Suppressor of Pathological Cardiac Hypertrophy.. Circ Res 130(10):1586-1600 PMID: 35437018
- 7. Wang P et al.. 2022. Elevated MCU Expression by CaMKIIδB Limits Pathological Cardiac Remodeling.. Circulation 145(14):1067-1083 PMID: 35167328
- 8. Yue P et al.. 2022. Yap1 modulates cardiomyocyte hypertrophy via impaired mitochondrial biogenesis in response to chronic mechanical stress overload.. Theranostics 12(16):7009-7031 PMID: 36276651
