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. 2018 Nov 1;315(5):H1434-H1442.
doi: 10.1152/ajpheart.00595.2017. Epub 2018 Jun 29.

Inhibition of programmed necrosis limits infarct size through altered mitochondrial and immune responses in the aged female rat heart

Alexandra M Garvin  1 , Morgan A Jackson  1 , Donna H Korzick  1   2
Affiliations

Inhibition of programmed necrosis limits infarct size through altered mitochondrial and immune responses in the aged female rat heart

Alexandra M Garvin et al. Am J Physiol Heart Circ Physiol. .

Abstract

Both advancing age and estrogen loss exacerbate acute myocardial infarction in the female heart. However, the mechanistic underpinnings of age-related differences in cell death after ischemia-reperfusion (I/R) injury in female subjects and reductions in cardioprotective reserve capacity remain largely unexplored. The aim of the present study was to determine the efficacy of programmed necrosis inhibition on infarct size reduction and preservation of left ventricular (LV) function after I/R injury with female aging. Fischer 344 rats were ovariectomized (OVX) at 15 mo and studied at 24 mo (MO OVX) versus adult rats with intact ovaries (6 mo) VSports手机版. After in vivo coronary artery ligation (55-min ischemia and 2- or 6-h reperfusion), necrostatin-1 (Nec-1; 3. 5 or 5. 7 mg/kg) delivered upon reperfusion significantly reduced infarct size by 37% and improved LV function in the MO OVX group ( P < 0. 01). Although age-associated elevations in cyclophilin D and mitochondrial acetylation ( P < 0. 001) were unaffected by Nec-1, profound reductions in IL-1, IL-6, and TNF-α ( P < 0. 05) as well as cardiac immune cell infiltration were observed in MO OVX but not adult rats. We conclude that chronic inflammation and postmenopausal estrogen deficiency conspire to exacerbate acute infarction through a mechanism involving exaggerated mitochondria-mediated programmed necrosis through receptor-interacting protein 1 signaling. Modulatory effects of programmed necrosis inhibition on proinflammatory cytokine production after I/R reveal a potentially important mechanistic target to restore and preserve cardiac function in the OVX aged female heart. NEW & NOTEWORTHY Myocardial infarct size reduction by inhibition of programmed necrosis in aged female subjects suggests a dominant cell death pathway. Alterations in mitochondrial protein levels and acetylation underscore a mitochondria-dependent mechanism, whereas the profound cytokine reduction in aged subjects alone points to a divergent role for immune modulation of programmed necrosis and viable therapeutic target. .

Keywords: aging; ischemic heart; mitochondria; programmed necrosis V体育安卓版. .

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"VSports注册入口" Figures

Fig. 1.
Fig. 1.
Myocardial infarct size after coronary artery ligation [55-min ischemia/2-h reperfusion (I/R) with or without necrostatin-1 (Nec-1)]. A−C: area at risk (AAR)/left ventricle (LV; A) and infarct/AAR (B) with representative triphenyltetrazolium chloride-stained images from rats ovariectomized (OVX) at 15 mo and studied at 24 mo (MO OVX) treated with vehicle versus Nec-1 treatment (C). Arrows denote significantly less necrotic cell death within the AAR after Nec-1. Data are presented as means ± SE; n = 3–5 per group. *P < 0.05, effect of MO OVX; †P < 0.01, I/R vs. I/R + Nec-1.
Fig. 2.
Fig. 2.
TUNEL-positive cells in the adult and aged groups after coronary artery ligation (55-min ischemia/6-h reperfusion) from the remote and border zone (BZ) areas (A) with representative images (B). Open bars, remote region; solid bars, BZ. OVX, ovariectomized; TMRE, tetramethylrhodamine, ethyl ester; TnI, troponin I. Data are presented as means ± SE; n = 4–5 per group. †P < 0.01, effect of ischemia-reperfusion injury vs. vehicle.
Fig. 3.
Fig. 3.
Heart rate [HR, in beats/min (bpm); A], left ventricular developed pressure (LVDP; B), and maximum dP/dt (C) after coronary artery ligation [55-min ischemia/6-h reperfusion (I/R) with or without necrostatin-1 (Nec-1)] or sham surgery. MO OVX, rats ovariectomized at 15 mo and studied at 24 mo. Data are presented as means ± SE; n = 3–5 per group. *P < 0.01, effect of MO OVX within treatment group (control, I/R, and I/R + nec-1); †P < 0.02 vs. control within age.
Fig. 4.
Fig. 4.
Cytosolic protein levels for receptor-interacting protein (RIP)1 (A) and RIP3 (B) after coronary artery ligation [55-min ischemia/6-h reperfusion (I/R) with or without necrostatin-1 (Nec-1)] or sham surgery were assessed by Western blot analysis. MO OVX, rats ovariectomized at 15 mo and studied at 24 mo. Data are presented as means ± SE; n = 4–5 per group. †P < 0.05 vs. sham within age; §P < 0.01, I/R vs. I/R + Nec-1.
Fig. 5.
Fig. 5.
Mitochondrial protein levels of cyclophilin D (CypD; A), sirtuin (SIRT)3 (B), and acetylated lysine (C) after coronary artery ligation [55-min ischemia/6-h reperfusion (I/R) with or without necrostatin-1 (Nec-1)] or sham surgery were assessed by Western blot analysis. MO OVX, rats ovariectomized at 15 mo and studied at 24 mo. Data are presented as means ± SE; n = 4–5 per group. *P < 0.001, effect of age within treatment group (control, I/R, and I/R + Nec-1); §P < 0.01, I/R vs. I/R + Nec-1.
Fig. 6.
Fig. 6.
Serum cytokine levels for IL-1 (A), IL-6 (B), and TNF-α (C) after coronary artery ligation [55-min ischemia/6-h reperfusion (I/R) with or without necrostatin-1 (Nec-1)] or sham surgery. MO OVX, rats ovariectomized at 15 mo and studied at 24 mo. Data are presented as means ± SE; n = 3–5 per group. †P < 0.05 vs. sham within age; §P < 0.05, I/R vs. I/R + Nec-1.
Fig. 7.
Fig. 7.
Hematoxylin and eosin-stained left ventricular tissue depicting immune cell infiltration after coronary artery ligation [55-min ischemia/6-h reperfusion (I/R) with or without necrostatin-1 (Nec-1)] or sham surgery. MO OVX, rats ovariectomized at 15 mo and studied at 24 mo.
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References

    1. Adameova A, Hrdlicka J, Szobi A, Farkasova V, Kopaskova K, Murarikova M, Neckar J, Kolar F, Ravingerová T, Dhalla NS. Evidence of necroptosis in hearts subjected to various forms of ischemic insults. Can J Physiol Pharmacol 95: 1163–1169, 2017. doi:10.1139/cjpp-2016-0609. - DOI - PubMed
    1. Bochaton T, Crola-Da-Silva C, Pillot B, Villedieu C, Ferreras L, Alam MR, Thibault H, Strina M, Gharib A, Ovize M, Baetz D. Inhibition of myocardial reperfusion injury by ischemic postconditioning requires sirtuin 3-mediated deacetylation of cyclophilin D. J Mol Cell Cardiol 84: 61–69, 2015. doi:10.1016/j.yjmcc.2015.03.017. - DOI - PubMed
    1. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248–254, 1976. doi:10.1016/0003-2697(76)90527-3. - DOI - PubMed
    1. Chakraborty TR, Gore AC. Aging-related changes in ovarian hormones, their receptors, and neuroendocrine function. Exp Biol Med (Maywood) 229: 977–987, 2004. doi:10.1177/153537020422901001. - DOI - PubMed
    1. Chan FK, Shisler J, Bixby JG, Felices M, Zheng L, Appel M, Orenstein J, Moss B, Lenardo MJ. A role for tumor necrosis factor receptor-2 and receptor-interacting protein in programmed necrosis and antiviral responses. J Biol Chem 278: 51613–51621, 2003. doi:10.1074/jbc.M305633200. - V体育官网 - DOI - PubMed

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