Cardioprotective Effects of HSP72 Administration on Ischemia-Reperfusion Injury

Abstract

BACKGROUND Although early reperfusion is the most desirable intervention after ischemic myocardial insult, it may add to damage through oxidative stress. OBJECTIVES We investigated the cardioprotective effects of a single intravenous dose of heat shock protein (HSP72) coupled to a single-chain variable fragment (Fv) of monoclonal antibody 3E10 (3E10Fv) in a rabbit ischemia-reperfusion model. The Fv facilitates rapid transport of HSP72 into cells, even with intact membranes. METHODS A left coronary artery occlusion (40 min), reperfusion (3 h) model was employed in 31 rabbits. Of these, 12 rabbits received the fusion protein (Fv-HSP72) intravenously. The remaining 19 control rabbits received a molar equivalent of 3E10Fv alone (n = 6), HSP72 alone (n = 6), or phosphate buffered saline (n = 7). Serial echocardiographic examinations were performed to assess left ventricular (LV) function before and after reperfusion. Micro-single photon emission computed tomography imaging of 99mTc-labeled annexin-V was performed with micro-computed tomography to characterize apoptotic damage in vivo, followed by gamma counting of the excised myocardial specimens to quantify cell death. Histopathological characterization of the myocardial tissue, and sequential cardiac troponin I measurements were also undertaken. RESULTS Myocardial annexin-V uptake was 43% lower in the area at risk (p = 0.0003) in Fv-HSP72-treated rabbits compared to controls receiving HSP72 or 3E10Fv alone. During reperfusion, troponin I release was 42% lower and the echocardiographic LV ejection fraction 27% higher in the Fv-HSP72-treated group compared to controls. Histopathological analyses confirmed penetration of 3E10Fv-containing molecules into cardiomyocytes in vivo, and treatment with Fv-HSP72 showed fewer apoptotic nuclei compared to control rabbits. CONCLUSIONS A single-dose administration of Fv-HSP72 fusion protein at the time of reperfusion reduced myocardial apoptosis almost by half, and improved LV functional recovery following myocardial ischemia-reperfusion injury in rabbits. It might have a potential to serve as an adjunct to early reperfusion in the management of myocardial infarction.

Single-Cell RNA Sequencing of the Cardiovascular System: New Looks for Old Diseases

“…As sudden death from myocardial infarction (MI) has decreased and more people are surviving MIs, there is a growing clinical need to attenuate the damage following MI to improve outcomes and prevent heart failure. Various strategies have been employed to reduce infarct size and preserve or even improve cardiac contractility (88)(89)(90). Neovascularization of coronary arteries at the infarct border following MI has been shown to improve myocardium outcomes (91,92).…”

The Role of O-GlcNAcylation for Protection against Ischemia-Reperfusion Injury

“…Elevating O-GlcNAc levels augments expression of HSPs by heat stress [14,95], while decreasing O-GlcNAc suppresses expression of HSPs [96]. Expression of HSP70 and HSP72 may be protective against IR injury through repression of apoptosis [97,98,99], because they are upregulated by a RIC stimulus [100]. Jones et al showed that HSP70 levels were increased in cardiomyocytes that were protected by PUGNAc against H 2 O 2 injury [20].…”

Heat shock protein 70: A promising therapeutic target for myocardial ischemia–reperfusion injury

“…Recent clinical trials on HSP70 have primarily examined the ability of HSP70 or HSP70 antibody to determine the prognosis of patients with acute coronary syndrome (Jenei et al, ; X. Zhang et al, ). Given that previous reports have successfully demonstrated the viability‐improved roles of HSP70 for stem cells (Chang et al, ) and the function of Fv‐HSP70 for the recovery of the left ventricular ejection fraction (Tanimoto et al, ), whether these treatments (and other potential therapeutic treatments) can elicit similar effects in clinical trials should be investigated. Collectively, it is worth verifying and applying what we found from animal models to human populations.…”