Beneficial impact of cardiac heavy metal scavenger metallothionein in sepsis-provoked cardiac anomalies dependent upon regulation of endoplasmic reticulum stress and ferroptosis but not autophagy.

Aims: Sepsis represents a profound proinflammatory response with a major contribution from oxidative injury. Here we evaluated possible impact of heavy metal scavenger metallothionein (MT) on endotoxin lipopolysaccharide (LPS)-induced oxidative stress, endoplasmic reticulum (ER) stress, autophagy, and ferroptosis enroute to myocardial injury along with interplay among these stress domains.
Materials and Methods: Echocardiographic, cardiomyocyte mechanical and intracellular Ca ²⁺ responses were monitored in myocardia from WT and transgenic mice with cardiac-selective MT overexpression challenged with LPS. Oxidative stress, stress signaling (p38, ERK, JNK), ER stress, autophagy, and ferroptosis were scrutinized.
Key Findings: RNAseq analysis revealed discrepant patterns in ferroptosis between LPS-exposed and normal murine hearts. LPS insult enlarged LV end systolic dimension, suppressed fractional shortening, ejection fraction, maximal velocity of shortening/relengthening and peak shortening, as well as elongated relengthening along with dampened intracellular Ca ²⁺ release and reuptake. In addition, LPS triggered oxidative stress (lowered glutathione/glutathione disulfide ratio and O ₂ ^- production), activation of stress cascades (p38, ERK, JNK), ER stress (GRP78, PERK, Gadd153, and IRE1α), inflammation (TNFα and iNOS), unchecked autophagy (LCB3, Beclin-1 and Atg7), ferroptosis (GPx4 and SLC7A11) and interstitial fibrosis. Although MT overexpression itself did not reveal response on cardiac function, it attenuated or mitigated LPS-evoked alterations in echocardiographic, cardiomyocyte contractile and intracellular Ca ²⁺ characteristics, O ₂ ^- production, TNFα level, ER stress and ferroptosis (without affecting autophagy, elevated AMP/ATP ratio, and iNOS). In vitro evidence revealed beneficial effects of suppression of oxidative stress, ER stress and ferroptosis against LPS-elicited myocardial anomalies.
Significance: These data strongly support the therapeutic promises of MT and ferroptosis in septic cardiomyopathy.
Competing Interests: Declaration of competing interest No potential conflict of interest exists for any authors.
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