Exogenous ubiquitin reduces inflammatory response and preserves myocardial function 3 days post-ischemia-reperfusion injury

Abstract

β-Adrenergic receptor (β-AR) stimulation increases extracellular levels of ubiquitin (UB) in myocytes, and exogenous UB decreases β-AR-stimulated myocyte apoptosis and myocardial fibrosis. Here, we hypothesized that exogenous UB modulates the inflammatory response, thereby playing a protective role in cardiac remodeling after ischemia-reperfusion (I/R) injury. C57BL/6 mice infused with vehicle or UB (1 μg·g−1·h−1) were subjected to myocardial I/R injury. Functional and biochemical parameters of the heart were examined 3 days post-I/R. Heart weight-to-body weight ratios were similarly increased in I/R and UB + I/R groups. The area at risk and infarct size were significantly lower in UB + I/R versus I/R groups. Measurement of heart function using echocardiography revealed that I/R decreases percent fractional shortening and percent ejection fraction. However, the decrease in fractional shortening and ejection fraction was significantly lower in the UB + I/R group. The UB + I/R group displayed a significant decrease in inflammatory infiltrates, neutrophils, and macrophages versus the I/R group. Neutrophil activity was significantly lower in the UB + I/R group. Analysis of the concentration of a panel of 23 cytokines/chemokines in the serum using a Bio-Plex assay revealed a significantly lower concentration of IL-12 subunit p40 in the UB + I/R versus I/R group. The concentration of monocyte chemotactic protein-1 was lower, whereas the concentration of macrophage inflammatory protein-1α was significantly higher, in the UB+I/R group versus the sham group. Expression of matrix metalloproteinase (MMP)-2 and activity of MMP-9 were higher in the UB + I/R group versus the I/R group. Levels of ubiquitinated proteins and tissue inhibitor of metalloproteinase 2 expression were increased to a similar extent in both I/R groups. Thus, exogenous UB plays a protective role in myocardial remodeling post-I/R with effects on cardiac function, area at risk/infarct size, the inflammatory response, levels of serum cytokines/chemokines, and MMP expression and activity.NEW & NOTEWORTHY Stimulation of β-adrenergic receptors increases extracellular levels of ubiquitin (UB) in myocytes, and exogenous UB decreases β-adrenergic receptor-stimulated myocyte apoptosis and myocardial fibrosis. Here, we provide evidence that exogenous UB decreases the inflammatory response and preserves heart function 3 days after myocardial ischemia-reperfusion injury. Further identification of the molecular events involved in the anti-inflammatory role of exogenous UB may provide therapeutic targets for patients with ischemic heart disease.

The Regulatory Role of T Cell Responses in Cardiac Remodeling Following Myocardial Infarction

“…Exogenous ubiquitin plays a protective role in attenuating the cardiac inflammatory response and decreasing infarct size after I/R injury. Moreover, exogenous ubiquitin increased the expression of MMP-2 and MMP-9, which can increase ECM degradation and can contribute to a reduction in infarct size [54]. Extracellular ubiquitin interacts with CXCR4 and affects the proliferation of cardiac fibrosis via the ERK 1/2 pathway [55,56].…”

Co‑expression of tissue kallikrein 1 and tissue inhibitor of matrix metalloproteinase 1 improves myocardial ischemia‑reperfusion injury by promoting angiogenesis and inhibiting oxidative stress

“…A previous study reported that a substantial increase in MMP9 and MMP2 expression levels was positively correlated with the degree of left ventricular fibrosis in a mouse model of pressure overload ( 23 ). Additionally, a previous study demonstrated that MMP9 and MMP2 expression levels were significantly increased in myocardial I/R model mice compared with sham mice ( 24 ). In the present study, compared with sham rats, MMP9 and MMP2 mRNA and protein expression levels were significantly increased following myocardial I/R injury, but significantly reduced following Ad-hTK1/hTIMP1 injection.…”

Effects and Mechanism of Noninvasive Positive-Pressure Ventilation in a Rat Model of Heart Failure Due to Myocardial Infarction

“…During IRI, the sudden release of oxygen molecules reactivates mitochondria and the electron transport chain, resulting in a significant increase in reactive oxygen species synthesis and activation of MMP-2 [ 26 ]. MMP-2 was proved to promote the degradation of cardiac troponin I and promote apoptosis, and inhibition of MMP-2 was helpful to prevent apoptosis [ 27 ]. Previous study also showed that MMP-2 was involved in the process of ventricular remodeling in HF, and is an independent predictive factor of death [ 28 ].…”