regulation of cardiac muscle hypertrophy in response to stress

Definition

Target type: biologicalprocess

Any process that modulates the frequency, rate or extent of cardiac muscle hypertrophy in response to stress. [GO_REF:0000058, GOC:BHF, GOC:rl, GOC:TermGenie, PMID:19287093]

Cardiac muscle hypertrophy, an increase in the size of cardiomyocytes, is a complex adaptive response to stress. The process is tightly regulated by a multitude of signaling pathways, involving both mechanical and biochemical stimuli.

**Mechanical Stimuli:** Increased workload, such as elevated blood pressure or increased afterload, triggers stretch-activated channels in the sarcolemma. This activates downstream signaling cascades, including the calcineurin pathway, leading to hypertrophic growth.

**Biochemical Stimuli:**
- **Hypertrophic Stimuli:**
- **Growth factors:** Hormones like Angiotensin II (AngII), Endothelin-1 (ET-1), and Insulin-like Growth Factor-1 (IGF-1) activate intracellular signaling pathways, including the MAPK (mitogen-activated protein kinase) and PI3K/AKT pathways, promoting hypertrophy.
- **Neurotransmitters:** Catecholamines like norepinephrine and epinephrine activate β-adrenergic receptors, leading to increased intracellular calcium and activation of the CaMKII (calcium/calmodulin-dependent protein kinase II) pathway, contributing to hypertrophy.
- **Anti-hypertrophic Stimuli:**
- **Natriuretic peptides:** Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) oppose hypertrophic signaling by activating cGMP-dependent protein kinase (PKG), inhibiting downstream pathways.

**Molecular Mechanisms:**
- **Transcriptional Regulation:** The signaling pathways converge on transcription factors, including GATA4, MEF2, and NFAT, that regulate the expression of genes involved in hypertrophy. These genes encode proteins for structural components (e.g., sarcomeric proteins), energy metabolism (e.g., mitochondrial proteins), and intracellular signaling molecules.
- **Protein Synthesis:** Increased protein synthesis is essential for hypertrophy. Hypertrophic stimuli activate the mTOR (mammalian target of rapamycin) pathway, promoting ribosome biogenesis and protein translation.

**Pathological Consequences:**
- While initially adaptive, prolonged or excessive hypertrophy can lead to maladaptive changes, including fibrosis, diastolic dysfunction, and eventually, heart failure.

**Regulation of Hypertrophy:**
- **Physiological Hypertrophy:** This type is a beneficial adaptation to increased workload, primarily involving the activation of the calcineurin pathway and the expression of genes related to sarcomeric proteins.
- **Pathological Hypertrophy:** This type is associated with chronic disease states like hypertension, heart failure, and cardiomyopathies. It is characterized by the activation of multiple signaling pathways, including the MAPK and PI3K/AKT pathways, and the expression of a broader spectrum of genes.

**Therapeutic Implications:**
- Understanding the molecular mechanisms of cardiac hypertrophy is crucial for the development of targeted therapies to prevent and treat cardiac diseases. Current therapeutic strategies focus on modulating signaling pathways, inhibiting hypertrophic growth, and promoting cardiac function.'
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