negative regulation of cardiac muscle hypertrophy

Definition

Target type: biologicalprocess

Any process that decreases the rate, frequency or extent of the enlargement or overgrowth of all or part of the heart due to an increase in size (not length) of individual cardiac muscle fibers, without cell division. [GOC:BHF, GOC:dph, GOC:tb]

Negative regulation of cardiac muscle hypertrophy is a complex process that involves a tightly regulated balance of signaling pathways and gene expression. It is essential for maintaining normal cardiac function and preventing pathological hypertrophy, which can lead to heart failure.

**Key Signaling Pathways Involved:**

* **Calcineurin/NFAT Pathway:** Calcineurin is a calcium-dependent phosphatase that activates the nuclear factor of activated T cells (NFAT). When activated, NFAT translocates to the nucleus and promotes the transcription of genes involved in cardiac hypertrophy.
* **MAPK Pathway:** Mitogen-activated protein kinases (MAPKs) are a family of serine/threonine kinases that play a critical role in cellular growth, differentiation, and stress responses. In the context of cardiac hypertrophy, MAPKs such as ERK1/2 and JNK can be activated by various stimuli and contribute to hypertrophic growth.
* **PI3K/Akt Pathway:** Phosphoinositide 3-kinase (PI3K) and its downstream effector Akt are involved in cell survival, growth, and metabolism. This pathway can promote cardiac hypertrophy by activating downstream targets such as mTOR, which regulates protein synthesis.
* **TGF-β Pathway:** Transforming growth factor-beta (TGF-β) is a pleiotropic cytokine that can have both pro- and anti-hypertrophic effects. TGF-β can activate Smad signaling, which can either promote or inhibit hypertrophy depending on the context.

**Mechanisms of Negative Regulation:**

* **Suppression of Hypertrophic Signaling:** Several mechanisms can negatively regulate the hypertrophic signaling pathways mentioned above. For example:
* **Calcineurin Inhibitors:** Drugs like cyclosporine and tacrolimus inhibit calcineurin activity, thereby suppressing NFAT activation and hypertrophy.
* **MAPK Inhibitors:** Specific inhibitors of MAPK kinases can attenuate hypertrophic signaling.
* **PI3K/Akt Inhibitors:** Pharmacological inhibitors or genetic knockout of PI3K or Akt can suppress hypertrophic growth.
* **Induction of Anti-hypertrophic Factors:** Several genes and proteins have been shown to have anti-hypertrophic effects. These include:
* **Cardiac-specific microRNAs:** Certain microRNAs, such as miR-29, have been shown to suppress hypertrophic gene expression.
* **Protein Phosphatases:** Protein phosphatases, such as PP1 and PP2A, can dephosphorylate and inactivate signaling proteins involved in hypertrophy.
* **Transcription Factors:** Transcription factors like GATA4 and MEF2 can bind to specific DNA sequences and regulate the expression of genes involved in cardiac development and function. Some of these factors can suppress hypertrophic gene expression.
* **Regulation of Cardiac Remodeling:** Negative regulation of hypertrophy also involves mechanisms that control the remodeling of the heart. This includes:
* **Apoptosis:** Programmed cell death, or apoptosis, can help to remove hypertrophic cardiomyocytes and prevent excessive growth.
* **Fibrosis:** While excessive fibrosis can contribute to heart failure, controlled fibrosis can help to maintain cardiac structure and function.
* **Mitochondrial Biogenesis:** Increased mitochondrial biogenesis can improve energy production and help to compensate for the increased demands of a hypertrophied heart.

**Clinical Relevance:**

Understanding the mechanisms of negative regulation of cardiac hypertrophy is crucial for developing novel therapies to prevent and treat heart failure. Several promising therapeutic strategies are currently under investigation, including:

* **Calcineurin Inhibitors:** While primarily used for immunosuppression, these drugs have shown potential for treating hypertrophic cardiomyopathy.
* **MAPK Inhibitors:** Several MAPK inhibitors are being investigated for their ability to reduce hypertrophic signaling.
* **MicroRNA Therapeutics:** The delivery of microRNAs that target hypertrophic genes is a potential therapeutic approach.

**Conclusion:**

Negative regulation of cardiac muscle hypertrophy is a complex process involving multiple signaling pathways, gene expression, and cellular processes. Understanding these mechanisms is essential for developing effective therapies to prevent and treat heart failure.'
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Proteins (3)

Compounds (24)