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Complement Destabilizes Cardiomyocyte Function In Vivo after Polymicrobial Sepsis and In Vitro
Miriam Kalbitz1, Fatemeh Fattahi2, Todd J Herron3
1Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; Department of Orthopedic Trauma, Hand, Plastic and Reconstructive Surgery, University Hospital of Ulm, 89081 Ulm, Germany;
Insights
Sepsis disrupts cardiomyocyte homeostasis, impairing heart function. Complement component 5a (C5a) exacerbates this by reducing key regulatory proteins and ion channel function, highlighting complement
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.
Abstract:
There is accumulating evidence during sepsis that cardiomyocyte (CM) homeostasis is compromised, resulting in cardiac dysfunction. An important role for complement in these outcomes is now demonstrated. Addition of C5a to electrically paced CMs caused prolonged elevations of intracellular Ca(2+) concentrations during diastole, together with the appearance of spontaneous Ca(2+) transients. In polymicrobial sepsis in mice, we found that three key homeostasis-regulating proteins in CMs were reduced: Na(+)/K(+)-ATPase, which is vital for effective action potentials in CMs, and two intracellular Ca(2+) concentration regulatory proteins, that is, sarcoplasmic/endoplasmic reticulum calcium ATPase 2 and the Na(+)/Ca(2+) exchanger. Sepsis caused reduced mRNA levels and reductions in protein concentrations in CMs for all three proteins. The absence of either C5a receptor mitigated sepsis-induced reductions in the three regulatory proteins. Absence of either C5a receptor (C5aR1 or C5aR2) diminished development of defective systolic and diastolic echocardiographic/Doppler parameters developing in the heart (cardiac output, left ventricular stroke volume, isovolumic relaxation, E' septal annulus, E/E' septal annulus, left ventricular diastolic volume). We also found in CMs from septic mice the presence of defective current densities for Ik1, l-type calcium channel, and Na(+)/Ca(2+) exchanger. These defects were accentuated in the copresence of C5a. These data suggest complement-related mechanisms responsible for development of cardiac dysfunction during sepsis.
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