Abstract
BackgroundThe secreted glycoprotein Slit2, previously known as an axon guidance cue, has recently been found to protect tissues in pathological conditions; however, it is unknown whether Slit2 functions in cardiac ischemia–reperfusion (IR) injury.MethodsLangendorff-perfused isolated hearts from Slit2-overexpressing (Slit2-Tg) mice and C57BL/6J mice (background strain) were subjected to 20 min of global ischemia followed by 40 min of reperfusion. We compared Slit2-Tg with C57BL/6J mice in terms of left ventricular function and infarct size of post-IR hearts along with tissue histological and biochemical assessments (mRNA and protein expression, phosphorylation status, and myofilament contractile properties).ResultsSlit2 played cardioprotective roles in maintaining contractile function and reducing infarct size in post-IR hearts. IR increased the expression of the Slit2 receptor Robo4 and the membrane receptor Slamf7, but these increases were suppressed by Slit2 overexpression post IR. This suppression was associated with inhibition of the nuclear translocation of NFκB p65 and reductions in IL-1β and IL-18 release into perfusates. Furthermore, Slit2 overexpression attenuated the increases in myofilament-associated PKCs and phosphorylation of cTnI at Ser43 in the post-IR myocardium. The myofilament calcium sensitivity and actomyosin MgATPase activity were preserved in the post-IR Slit2 myocardium.ConclusionOur work demonstrates that Slit2 inhibits inflammatory responses and maintains myofilament contractile properties, thus contributing, at least in part, to the prevention of structural and functional damage during IR.
Highlights
WHO statistics indicate that the annual deaths from ischemic heart disease were ∼8.9 million worldwide in 2017 (GBD 2017; Causes of Death Collaborators, 2018), despite the availability of various drugs and other therapeutic approaches that have been developed to tackle this epidemic condition (Hausenloy and Yellon, 2013)
Cardiac contractile function is executed by myofilaments, including thin filaments [actin, tropomyosin, and the troponin complex of cardiac troponin C, cardiac troponin I, and cardiac troponin T] and thick filaments [myosin heavy and light chains, myosin binding protein C (MyBP-C), and titin] and regulated by the balance of myofilament phosphorylation (Metzger and Westfall, 2004; Verduyn et al, 2007; Kooij et al, 2010)
There were no significant differences in cardiac function (HR, left ventricular developed pressure (LVDP), and rate of pressure product (RPP)) between C57BL/6J and Slit2-Tg mice at baseline (0–20 min, Figures 1C–E)
Summary
WHO statistics indicate that the annual deaths from ischemic heart disease were ∼8.9 million worldwide in 2017 (GBD 2017; Causes of Death Collaborators, 2018), despite the availability of various drugs and other therapeutic approaches that have been developed to tackle this epidemic condition (Hausenloy and Yellon, 2013). Inflammatory response is the primary mechanism of IR injury, in which reperfusion triggers leukocyte recruitment and reactive oxygen species (ROS) production in endothelial cells. Transcriptional factors such as NFκB activate the expression of proinflammatory cytokines TNF-α, IL-1β, IL-6, and IL-18 (Barnes and Karin, 1997; Kawaguchi et al, 2011; Burma et al, 2014; Lu et al, 2016). Protein kinase signaling has been explored as a therapeutic target for improvement of cardiac function in heart disease (Singh et al, 2017). The secreted glycoprotein Slit, previously known as an axon guidance cue, has recently been found to protect tissues in pathological conditions; it is unknown whether Slit functions in cardiac ischemia–reperfusion (IR) injury
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