Ca²⁺/Calmodulin-Dependent Protein Kinase II and Androgen Signaling Pathways Modulate MEF2 Activity in...

Area of Science:

• Cardiovascular Biology
• Molecular Endocrinology
• Cell Signaling

Background:

• Testosterone induces cardiac hypertrophy via androgen receptor (AR)-dependent and -independent pathways.
• Molecular mechanisms underlying androgen action in the heart remain poorly understood.
• Calcium/calmodulin-dependent protein kinase II (CaMKII) and myocyte-enhancer factor 2 (MEF2) are critical for cardiac myocyte growth.

Purpose of the Study:

• To investigate the molecular mechanisms by which testosterone affects CaMKII and MEF2 in cardiac myocyte hypertrophy.
• To elucidate the roles of CaMKII and AR signaling in testosterone-induced cardiac hypertrophy.

Main Methods:

• Studies on cultured rat cardiac myocytes and hearts from orchiectomized (ORX) rats.
• Monitoring MEF2 activity using a luciferase reporter plasmid.
• Utilizing siRNAs and pharmacological inhibitors for CaMKII, MEF2C, and AR pathways.
• In vivo studies with testosterone administration to ORX rats.
• Assessing cardiac hypertrophy markers, protein phosphorylation (CaMKII, PLN), and protein levels (MEF2C, AR) via Western blotting and ELISA.

Main Results:

• Testosterone increased CaMKII and phospholamban (PLN) phosphorylation in cardiac myocytes in a time- and concentration-dependent manner.
• Testosterone-induced MEF2 activity and cardiac myocyte hypertrophy were blocked by inhibiting CaMKII, MEF2C, and AR signaling.
• Testosterone administration to ORX rats increased CaMKII and PLN phosphorylation, and AR and MEF2 protein levels in hypertrophied hearts.

Conclusions:

• Testosterone activates MEF2 through CaMKII and AR signaling pathways.
• Testosterone-induced cardiac myocyte hypertrophy involves an orchestrated mechanism of signal transduction and transcription pathways.
• This study provides the first evidence for testosterone's activation of MEF2 via CaMKII and AR signaling in the heart.