Calcium-regulated transcriptional pathways in the normal and pathologic heart

Area of Science:

• Cardiology
• Molecular Biology
• Cellular Physiology

Background:

• Cytosolic calcium concentration ([Ca(2+)]) regulates vital cellular processes including signaling, metabolism, and muscle contraction.
• In cardiomyocytes, calcium (Ca2+) is crucial for electrophysiology, excitation-contraction coupling, contractile protein activity, metabolism, cell death, and transcriptional regulation via Ca2+-dependent pathways.

Purpose of the Study:

• To review the role of Ca2+ signaling pathways in regulating cardiac gene expression.
• To analyze the interplay between these pathways and their specificity in cardiac hypertrophy (CH) and heart failure (HF).
• To highlight novel strategies, specifically SERCA2a gene therapy, for correcting Ca2+ handling defects.

Main Methods:

• Literature review focusing on Ca2+ signaling, cardiac gene expression, CH, and HF.
• Analysis of established Ca2+-dependent pathways: Ca2+/calmodulin-calcineurin-NFAT and Ca2+/calmodulin-dependent kinases-MEF2.
• Examination of Ca2+ handling abnormalities in failing hearts and their impact on gene expression.

Main Results:

• CH and HF involve significant alterations in Ca2+ handling, including reduced sarcoplasmic reticulum Ca2+ content and impaired Ca2+ removal.
• These alterations lead to decreased contractility and are associated with reduced SERCA2a levels and a fetal gene program.
• Two primary Ca2+-dependent transcriptional pathways, NFAT and MEF2, are involved in regulating cardiac genes.

Conclusions:

• Dysfunctional Ca2+ handling is central to cardiac hypertrophy and heart failure pathogenesis.
• Understanding the complex Ca2+ signaling network is critical for developing effective therapies.
• SERCA2a gene therapy presents a promising avenue for restoring Ca2+ homeostasis and improving cardiac function.