Abstract
BackgroundSepsis is a systemic inflammatory response to a local severe infection that may lead to multiple organ failure and death. Previous studies have shown that 40–50% of patients with sepsis have diverse myocardial injuries and 70 to 90% mortality rates compared to 20% mortality in patients with sepsis without myocardial injury. Therefore, uncovering the mechanism of sepsis-induced myocardial injury and finding a target-based treatment are immensely important.ObjectiveThe present study elucidated the mechanism of sepsis-induced myocardial injury and examined the value of human umbilical cord mesenchymal stem cells (huMSCs) for protecting cardiac function in sepsis.MethodsWe used cecal ligation and puncture (CLP) to induce sepsis in mice and detect myocardial injury and cardiac function using serological markers and echocardiography. Cardiomyocyte apoptosis and heart tissue ultrastructure were detected using TdT-mediated dUTP Nick-End Labeling (TUNEL) and transmission electron microscopy (TEM), respectively. Fura-2 AM was used to monitor Ca2+ uptake and efflux in mitochondria. FQ-PCR and Western blotting detected expression of mitochondrial Ca2+ distribution regulators and PTEN-induced putative kinase 1 (PINK1). JC-1 was used to detect the mitochondrial membrane potential (Δψm) of cardiomyocytes.ResultsWe found that expression of PINK1 decreased in mouse hearts during sepsis, which caused cardiomyocyte mitochondrial Ca2+ efflux disorder, mitochondrial calcium overload, and cardiomyocyte injury. In contrast, we found that exosomes isolated from huMSCs (huMSC-exo) carried Pink1 mRNA, which could be transferred to recipient cardiomyocytes to increase PINK1 expression. The reduction in cardiomyocyte mitochondrial calcium efflux was reversed, and cardiomyocytes recovered from injury. We confirmed the effect of the PINK1-PKA-NCLX axis on mitochondrial calcium homeostasis in cardiomyocytes during sepsis.ConclusionThe PINK1-PKA-NCLX axis plays an important role in mitochondrial calcium efflux in cardiomyocytes. Therefore, PINK1 may be a therapeutic target to protect cardiomyocyte mitochondria, and the application of huMSC-exo is a promising strategy against sepsis-induced heart dysfunction.
Highlights
Sepsis is a systemic inflammatory response to a local severe infection that may lead to multiple organ failure and death, especially in patients with cardiac dysfunction, which increases mortality to 70–90% compared to patients without cardiac dysfunction [1]
We found that expression of PTEN-induced putative kinase 1 (PINK1) decreased in mouse hearts during sepsis, which caused cardiomyocyte mitochondrial Ca2+ efflux disorder, mitochondrial calcium overload, and cardiomyocyte injury
We found that the serum markers of cardiomyocyte injury (HBDH, creatine kinase (CK) and Cardiac troponin-I (cTnI)) increased significantly after cecal ligation and puncture (CLP) (Fig. 1d, α-Hydroxybutyrate dehydrogenase (HBDH): CLP 12 h group 1210 ± 246.2 versus sham group 158.2 ± 14.41, p < 0.0001; CK: CLP 12 h group 14,238 ± 2293 versus sham group 2229 ± 582.7, p < 0.0001; cTnI: CLP 12 h group 115.1 ± 30.8 versus sham group 36.35 ± 7.167, p < 0.0001), which indicated that sepsis induced cardiomyocyte injury in the first 12 h
Summary
Sepsis is a systemic inflammatory response to a local severe infection that may lead to multiple organ failure and death, especially in patients with cardiac dysfunction, which increases mortality to 70–90% compared to patients without cardiac dysfunction [1]. Sepsis-induced cardiac injury or dysfunction subsequently contributes to cardiovascular collapse, which results in poor perfusion of blood into multiple tissues [2]. The mechanisms underlying cardiac dysfunction in sepsis are not completely understood but include the following main mechanisms: (a) increased release of proinflammatory cytokines [3], (b) apoptotic myocardial cell death via activation of extrinsic and intrinsic pathways, (c) metabolic disorders and inducible nitric oxide synthase (NOS)-dependent action [4], (d) cardiacdepressant action of lysozyme c primarily originating from disintegrating neutrophils and monocytes [5], and (e) mitochondrial dysfunction [6, 7]. Sepsis is a systemic inflammatory response to a local severe infection that may lead to multiple organ failure and death. Uncovering the mechanism of sepsis-induced myocardial injury and finding a target-based treatment are immensely important
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