Myocardial alpha-thrombin receptor activation induces hypertrophy and increases atrial natriuretic factor gene...

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Protease Signaling

Background:

• Alpha-thrombin (alpha Th) influences myocardial contractility, a characteristic of hypertrophy-inducing agents.
• The presence of alpha Th receptors (alpha Th-R) on cardiac myocytes and alpha Th's long-term effects on cell growth and gene expression remain uncharacterized.

Purpose of the Study:

• To investigate whether cardiac myocytes express alpha Th receptors.
• To determine if long-term alpha Th treatment enhances myocyte growth and gene expression.
• To elucidate the signaling pathways involved in alpha Th-induced cardiac myocyte hypertrophy and gene regulation.

Main Methods:

• Primary neonatal rat ventricular myocytes were analyzed for alpha Th-R mRNA expression using a specific probe.
• Cells were treated with alpha Th, alpha Th-R agonist/non-agonist peptides, and specific inhibitors (protease, PKC, tyrosine kinase inhibitors).
• Hypertrophy, sarcomeric organization, and atrial natriuretic factor (ANF) expression were assessed; transcriptional activity was confirmed via transfection experiments.

Main Results:

• Neonatal rat ventricular myocytes express a 3.6-kb mRNA for alpha Th-R.
• Alpha Th induced myocyte hypertrophy, sarcomeric organization, and enhanced ANF expression, which were blocked by a specific protease inhibitor.
• An alpha Th-R agonist peptide activated ANF expression, while a non-agonist peptide did not; inhibition studies revealed the involvement of protein kinase C and tyrosine kinases.

Conclusions:

• Cardiac myocytes possess functional alpha Th receptors that mediate the effects of alpha Th.
• Alpha Th-induced myocyte hypertrophy and ANF expression are dependent on protein kinase C and tyrosine kinase signaling pathways.
• Extracellular proteases like alpha Th represent novel regulators of myocardial cell gene expression and growth.