AM₁‐receptor‐dependent protection by intermedin of human vascular and cardiac non‐vascular cells from ischaemia–reperfusion injury

Abstract

Key points• Coronary artery disease occurs when fatty deposits cause obstruction to blood flow in the coronary arteries, reducing the supply of blood to the heart. This can damage the heart muscle (heart attack).• In this study, a small protein named intermedin is shown to be present in cells from the human heart and blood vessels.• Intermedin, acting on a specific type of receptor protein shown to be present on the surface of these cells, is found to protect against damage occurring during experiments conducted in human cardiac and vascular cells in culture under conditions designed to simulate initial obstruction and subsequent restoration of blood flow, respectively.• These results suggest that administration of intermedin might provide a novel therapeutic strategy to minimise damage to heart muscle following a heart attack.Abstract Intermedin (IMD) protects rodent heart and vasculature from oxidative stress and ischaemia. Less is known about distribution of IMD and its receptors and the potential for similar protection in man. Expression of IMD and receptor components were studied in human aortic endothelium cells (HAECs), smooth muscle cells (HASMCs), cardiac microvascular endothelium cells (HMVECs) and fibroblasts (v-HCFs). Receptor subtype involvement in protection by IMD against injury by hydrogen peroxide (H 2 O 2 , 1 mmol l −1 ) and simulated ischaemia and reperfusion were investigated using receptor component-specific siRNAs. IMD and CRLR, RAMP1, RAMP2 and RAMP3 were expressed in all cell types. When cells were treated with 1 nmol l −1 IMD during exposure to 1 mmol l −1 H 2 O 2 for 4 h, viability was greater vs. H 2 O 2 alone (P < 0.05 for all cell types). Viabilities under 6 h simulated ischaemia differed (P < 0.05) in the absence and presence of 1 nmol l −1 IMD: HAECs 63% and 85%; HMVECs 51% and 68%; v-HCFs 42% and 96%. IMD 1 nmol l −1 present throughout ischaemia (3 h) and reperfusion (1 h) attenuated injury (P < 0.05): viabilities were 95%, 74% and 82% for HAECs, HMVECs and v-HCFs, respectively, relative to those in the absence of IMD (62%, 35%, 32%, respectively). When IMD 1 nmol l −1 was present during reperfusion only, protection was still evident (P < 0.05, 79%, 55%, 48%, respectively). Cytoskeletal disruption and protein carbonyl formation followed similar patterns. Pre-treatment (4 days) of HAECs with CRLR or RAMP2, but not RAMP1 or RAMP3, siRNAs abolished protection by IMD (1 nmol l −1 ) against ischaemia-reperfusion injury. IMD protects human vascular and cardiac non-vascular cells from oxidative stress and ischaemia-reperfusion, predominantly via AM 1 receptors.D. Bell and M. Campbell are joint first authors.

Adrenomedullin 2/intermedin: a putative drug candidate for treatment of cardiometabolic diseases

“…In isolated hearts, ADM2/IMD 1–40 , ADM2/IMD 1–47 and ADM2/IMD 1–53 ameliorated the I/R‐induced myocardial injury and decreased cardiac function (Yang et al , ). Further studies have shown that ADM2/IMD 1–47 protects cardiomyocytes and cardiac microvascular endothelium from I/R‐induced injury via AM 1 receptors (Bell et al , ; Bell et al , ).…”

Intermedin protects against myocardial ischemia-reperfusion injury in diabetic rats

“…Among the three degraded fragments, IMD1–53 exhibits the most potent biological cardiovascular effect [11]. IMD has been shown to have pathophysiological effect in multiple disease processes involving the circulatory and renal systems [12] and congestive heart failure [13]. IMD augments cardiac contractility [14], inhibits collagen synthesis, attenuates proliferation of cardiac fibroblasts [15], and attenuates cardiomyocyte hypertrophy [16].…”

“…Recently, intermedin has been demonstrated to protect human macrovascular, microvascular, and cardiac non-vascular cells against I/R injury via AM(1)-receptor signaling [12]. Furthermore, IMD1–53 exerts potent cardioprotective effects against acute rat ischemic injury [17], inhibiting endoplasmic reticulum stress via PI3 kinase-Akt signaling [18], and activating cardioprotective Akt/GSK-3beta signaling, decreasing mitochondrial-mediated myocardial apoptosis [19].…”

Implication of plasma intermedin levels in patients who underwent first-time diagnostic coronary angiography: a single centre, cross-sectional study

“…On cell level it has been shown that intermedin protects human macrovascular, microvascular, and cardiac non-vascular cells against ischemia reperfusion injury via AM(1)-receptor signaling [ 20 ]. Furthermore, IMD exerts potent cardioprotective effects against acute rat ischemic injury [ 21 ], inhibiting endoplasmic reticulum stress via PI3 kinase-Akt signaling [ 22 ], and activating cardioprotective Akt/GSK-3beta signaling, decreasing mitochondrial-mediated myocardial apoptosis [ 23 ].…”