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Published on: December 3, 2021
Distinct Myocardial Mechanisms Underlie Cardiac Dysfunction in Endotoxemic Male and Female Mice
Ion A Hobai1, Kanwal Aziz, Emmanuel S Buys
1*Cardiovascular Medicine, Department of Medicine, Boston University Medical Center, Boston, Massachusetts †Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard University, Boston, Massachusetts ‡Department of Biomedical Molecular Biology, Ghent University, and Inflammation Research Center, Flanders Institute for Biotechnology (VIB), Ghent, Belgium.
Insights
Sepsis causes heart dysfunction differently in male and female mice. In males, it affects calcium handling, while in females, it impacts muscle contraction sensitivity, with soluble guanylyl cyclase playing a role in females.
Area of Science:
- Cardiovascular Physiology
- Sepsis Pathophysiology
- Sex-Specific Biology
Background:
- Sepsis-induced cardiomyopathy in males involves impaired myocardial calcium (Ca) handling and sarcoplasmic reticulum Ca ATP-ase (SERCA) inhibition.
- cGMP, produced by soluble guanylyl cyclase (sGC), partially counteracts these effects in males.
- Mechanisms of sepsis-induced cardiomyopathy in female mice remain largely unknown.
Purpose of the Study:
- To investigate sex-specific mechanisms of sepsis-induced cardiomyopathy.
- To determine the role of calcium handling and sGC in female mice during sepsis.
- To compare myocardial responses to lipopolysaccharide (LPS) between male and female mice.
Main Methods:
- Utilized male and female C57Bl/6J mice (WT) and sGC α1 subunit deficient (sGCα1) mice.
- Administered lipopolysaccharide (LPS) to induce sepsis and assessed mortality and cardiac function (left ventricular ejection fraction) via echocardiography.
- Measured cardiomyocyte sarcomere shortening and intracellular Ca transients (ΔCai) in isolated cardiomyocytes.
Main Results:
- LPS induced similar mortality and cardiomyopathy in WT males, WT females, and sGCα1 males, but less severe effects in sGCα1 females.
- In male mice, LPS decreased ΔCai and SERCA activity, consistent with previous findings.
- In female mice, LPS depressed sarcomere shortening without altering ΔCai or SERCA activity, suggesting downstream effects on myofilament Ca sensitivity, partially mediated by sGC/cGMP.
Conclusions:
- Sepsis-induced cardiomyopathy exhibits distinct sex-specific mechanisms.
- In males, LPS impairs cardiac function via decreased ΔCai, independent of sGC.
- In females, LPS affects cardiac function downstream of ΔCai, potentially through sGC-dependent myofilament dysfunction.
Abstract:
In male mice, sepsis-induced cardiomyopathy develops as a result of dysregulation of myocardial calcium (Ca) handling, leading to depressed cellular Ca transients (ΔCai). ΔCai depression is partially due to inhibition of sarcoplasmic reticulum Ca ATP-ase (SERCA) via oxidative modifications, which are partially opposed by cGMP generated by the enzyme soluble guanylyl cyclase (sGC). Whether similar mechanisms underlie sepsis-induced cardiomyopathy in female mice is unknown.Male and female C57Bl/6J mice (WT), and mice deficient in the sGC α1 subunit activity (sGCα1), were challenged with lipopolysaccharide (LPS, ip). LPS induced mouse death and cardiomyopathy (manifested as the depression of left ventricular ejection fraction by echocardiography) to a similar degree in WT male, WT female, and sGCα1 male mice, but significantly less in sGCα1 female mice. We measured sarcomere shortening and ΔCai in isolated, externally paced cardiomyocytes, at 37°C. LPS depressed sarcomere shortening in both WT male and female mice. Consistent with previous findings, in male mice, LPS induced a decrease in ΔCai (to 30 ± 2% of baseline) and SERCA inhibition (manifested as the prolongation of the time constant of Ca decay, τCa, to 150 ± 5% of baseline). In contrast, in female mice, the depression of sarcomere shortening induced by LPS occurred in the absence of any change in ΔCai, or SERCA activity. This suggested that, in female mice, the causative mechanism lies downstream of the Ca transients, such as a decrease in myofilament sensitivity for Ca. The depression of sarcomere shortening shortening after LPS was less severe in female sGCα1 mice than in WT female mice, indicating that cGMP partially mediates cardiomyocyte dysfunction.These results suggest, therefore, that LPS-induced cardiomyopathy develops through distinct sex-specific myocardial mechanisms. While in males LPS induces sGC-independent decrease in ΔCai, in female mice LPS acts downstream of ΔCai, possibly via sGC-dependent myofilament dysfunction.
