Complement Destabilizes Cardiomyocyte Function In Vivo after Polymicrobial Sepsis and In Vitro.

Area of Science:

• Cardiovascular Physiology
• Immunology
• Sepsis Pathophysiology

Background:

• Sepsis frequently leads to cardiomyocyte (CM) dysfunction and compromised cardiac homeostasis.
• The role of the complement system, particularly C5a, in sepsis-induced cardiac dysfunction is increasingly recognized.

Purpose of the Study:

• To investigate the impact of complement component 5a (C5a) on cardiomyocyte homeostasis during sepsis.
• To elucidate the mechanisms by which C5a contributes to sepsis-related cardiac dysfunction in mice.

Main Methods:

• Electrically paced cardiomyocytes were exposed to C5a.
• Polymicrobial sepsis was induced in mice.
• Quantification of key protein and mRNA levels (Na+/K+-ATPase, SERCA2, Na+/Ca2+ exchanger) in cardiomyocytes.
• Assessment of cardiac function using echocardiography and Doppler parameters.
• Analysis of ion channel current densities (Ik1, L-type calcium channel, Na+/Ca2+ exchanger) in cardiomyocytes.

Main Results:

• C5a exposure prolonged diastolic intracellular Ca(2+) and induced spontaneous Ca(2+) transients in cardiomyocytes.
• Sepsis reduced Na+/K+-ATPase, SERCA2, and Na+/Ca2+ exchanger protein and mRNA levels in cardiomyocytes.
• Absence of C5a receptors (C5aR1 or C5aR2) mitigated sepsis-induced reductions in these proteins and improved cardiac function parameters.
• Sepsis impaired ion channel current densities, an effect exacerbated by C5a.

Conclusions:

• Complement component 5a plays a significant role in sepsis-induced cardiomyocyte dysfunction.
• C5a contributes to cardiac dysfunction by disrupting ion homeostasis and reducing key regulatory proteins.
• Targeting complement pathways may offer therapeutic strategies for sepsis-induced cardiac dysfunction.