Adrenomedullin Improves Cardiac Expression of Heat-Shock Protein 72 and Tolerance against Ischemia/Reperfusion Injury in Insulin-Resistant Rats

Abstract

We recently reported that long-term treatment with pioglitazone restored cardiac Akt phosphorylation in response to hyperthermia (HT) and subsequent cardiac heat-shock protein 72 (HSP72) expression, in heredity insulin resistance rats via improvement of insulin sensitivity. Because adrenomedullin (AM) promotes Akt phosphorylation and attenuates myocardial ischemia/reperfusion injury, we tested the hypothesis that pretreatment with AM before HT could restore depressed Akt activation and cardiac HSP72 expression, thereby enhancing protection against ischemia/reperfusion injury in this model. At 16 wk of age, male insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rats and control Long-Evans Tokushima Otsuka (LETO) rats were treated with AM (0.05 microg/kg . /min iv) or vehicle for 60 min. Thereafter, HT (43 C for 20 min) or normothermia (NT; 37 C for 20 min) was applied. The heart was isolated 1 and 24 h after HT. 1) Either AM or HT induced myocardial Akt phosphorylation in a phosphatidylinositol 3-kinase-dependent manner, which was augmented by their combination. 2) Akt phosphorylation induced by HT, or a combination of HT and AM, was attenuated in insulin-resistant OLETF rat hearts. 3) The levels of Akt phosphorylation in response to AM and/or HT correlated with reperfusion-induced left ventricular functional recovery and amount of released creatine kinase during reperfusion. 4) AM protected the hearts of OLETF rats and LETO rats. Our results suggest that AM pretreatment could enhance HT-induced myocardial Akt phosphorylation and subsequent HSP72 expression in a phosphatidylinositol 3-kinase-dependent manner, in association with tolerance against ischemia/reperfusion injury. This intervention was effective even in insulin-resistant hearts.

Repression of Human Papillomavirus Oncogene Expression under Hypoxia Is Mediated by PI3K/mTORC2/AKT Signaling

“…Collectively, the proteome data indicate that the regulation of several proteins is partially or fully reverted when hypoxic cells are treated with AKTi VIII or high glucose. These proteins include factors that are directly linked to the PI3K/AKT signaling pathway, such as adrenomedullin (ADM) (51), FAM57A (CT120) (52), or metallothionein 2A (MT2A) (53). Furthermore, two inhibitors of canonical Wnt signaling, Wnt5a (54) and DKK1 (55), were significantly downregulated under hypoxia in an AKT- and glucose-dependent manner, providing a possible link between AKT and the canonical Wnt signaling pathway under hypoxia.…”

Myocardial AKT: The Omnipresent Nexus

“…Similarly, activation of a membrane-bound estrogen receptor or inhibition of the non-long terminal repeat retrotransposon long interspersed nuclear element 1 (LINE-1, L1) in the ischemic heart increases AKT expression and phosphorylation and functional recovery following reperfusion (151, 433). Besides steroids, peptido-hormones including adiponectin, adrenomedullin, or growth hormone releasing hormone reduce myocardial injury in an AKT-dependent manner (235, 240, 634). Stimulation of GPCRs, e.g., by SDF-1 α , also mediates AKT phosphorylation and prevents myocardial cell death (572).…”

Adrenomedullin deficiency potentiates hyperoxic injury in fetal human pulmonary microvascular endothelial cells

“…al demonstrated that a constitutively active form of Akt is sufficient to protect adult mice from hyperoxic lung injury [22]. Interestingly, AM is shown to regulate prosurvival properties of endothelial progenitor [23] and cardiac [24] cells via Akt activation.…”