Cardiac contractile dysfunction and protein kinase C-mediated myofilament phosphorylation in disease and aging

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Heart Failure Pathophysiology

Background:

• Elevated protein kinase C (PKC) activity is linked to reduced cardiac function in heart failure.
• The role of downstream myofilament phosphorylation, specifically cardiac troponin I (cTnI) at serine 44 (S44), in this process remains debated.

Purpose of the Study:

• To investigate the expression of PKC isoforms and the phosphorylation status of cTnI at S44 (p-S44) in failing human myocardium.
• To assess the impact of pressure overload and aging on cardiac dysfunction and cTnI p-S44 in rat models.
• To evaluate the therapeutic potential of targeting PKCα activity on cardiac function.

Main Methods:

• Analysis of PKC isoform expression, cTnI p-S44 levels, and contractile function in failing human myocardium and in rat models of cardiac dysfunction.
• Utilizing ventricular assist device support in human subjects and gene transfer of dominant-negative PKCα (PKCαDN) in human myocytes.
• Examining cTnI phosphorylation and myocyte function in pressure-overloaded and aged rats.

Main Results:

• Failing human myocardium showed increased PKCα expression and cTnI p-S44 prior to ventricular assist device implantation.
• Circulatory support and PKCαDN gene transfer in human myocytes reduced PKCα, cTnI p-S44, and improved contractile function.
• Heightened cTnI phosphorylation at the analogous residue correlated with reduced myocyte function in rat models of pressure overload and aging.

Conclusions:

• PKC-mediated cTnI p-S44 is associated with cardiac cellular dysfunction in human and animal heart failure models.
• Intervention targeting PKCα activity decreases cTnI p-S44 and partially restores cardiac function.
• cTnI p-S44 represents a potential therapeutic target for improving contractile function in heart failure.