Parathyroid Hormone-Related Peptide and Its Analog, Abaloparatide, Attenuate Lethal Myocardial Ischemia-Reperfusion Injury

Abstract

Parathyroid hormone-related peptide (PTHrP) is well-known to play a role in bone formation, and abaloparatide, an analog of PTHrP(1-34), is approved for the treatment of osteoporosis in post-menopausal women. PTHrP has also been reported to have cardiovascular effects, with recent data demonstrating that exogenously administered PTHrP can limit the death of isolated cardiomyocytes subjected to oxidative stress via upregulation of classic ‘survival kinase’ signaling. Our aim in the current study was to extend this concept and, employing both in vitro and in vivo models, establish whether PTHrP(1-36) and abaloparatide are cardioprotective in the setting of lethal myocardial ischemia-reperfusion injury. We report that preischemic administration of PTHrP(1-36) and abaloparatide attenuated cell death in HL-1 cardiomyocytes subjected to simulated ischemia-reperfusion, an effect that was accompanied by the augmented expression of phospho-ERK and improved preservation of phospho-Akt, and blocked by co-administration of the MEK-ERK inhibitor PD98059. Moreover, using the translationally relevant swine model of acute coronary artery occlusion-reperfusion, we make the novel observation that myocardial infarct size was significantly reduced in pigs pretreated with PTHrP(1-36) when compared with placebo-controls (13.1 ± 3.3% versus 42.0 ± 6.6% of the area of at-risk myocardium, respectively; p < 0.01). Taken together, these data provide the first evidence in support of the concept that pretreatment with PTHrP(1-36) and abaloparatide renders cardiomyocytes resistant to lethal myocardial ischemia-reperfusion injury.

Keywords: abaloparatide; cardioprotection; infarct size; ischemia-reperfusion injury; myocardial infarction; myocardial ischemia; parathyroid hormone-related peptide.

Figure 1

Effect of PTHrP(1-36) (PTHrP: Panel A), abaloparatide (Abalo: Panel B) and concurrent assessment of PTHrP(1-36) and Abalo (Panel C) on viability of HL-1 cardiomyocytes maintained under normoxic conditions (left panels) or subjected to simulated ischemia-reperfusion (right panels). Data reported as mean ± SEM. * p < 0.05, ** p < 0.01 versus matched vehicle-control group; + p < 0.05 versus Abalo 0.1 nM, 1 nM and 100 nm; ★ p < 0.05 versus Abalo 100 nM, PTHrP 10 nM and PTHrP 100 nM.

Figure 2

Effect of PTHrP(1-36) (PTHrP) and abaloparatide (Abalo) on phospho-Akt and phospho-ERK expression in HL-1 cells subjected to simulated ischemia-reperfusion. (A) original immunoblots; (B) Mean phospho-Akt expression (normalized to GAPDH), mean phospho-ERK expression (normalized to total ERK) ± SEM. * p < 0.05, ** p < 0.01 versus control group.

Figure 3

Effect of vehicle, PTHrP(1-36) (PTHrP), abaloparatide (Abalo), PD998059 (PD) + vehicle, PD98059 + PTHrP or PD98059 + Abalo on viability of HL-1 cardiomyocytes maintained under normoxic conditions (left panel) or subjected to simulated ischemia-reperfusion (right panel). Data reported as mean ± SEM.

Figure 4

Plasma PTHrP concentration (ng/mL) in anesthetized pigs during the initial 2 h following subcutaneous injection. Data reported as mean ± SEM.

Figure 5

Heart rate, systolic and diastolic pressures, measured at baseline, 15 min, 1 h and 3 h (end) following reperfusion in PTHrP(1-36)-treated pigs and vehicle-controls. Data reported as mean ± SEM; no significant differences between groups.

Figure 6

Myocardial infarct size in PTHrP(1-36)-treated pigs and vehicle-controls. (Top panel) individual data points and mean values ± SEM. (Bottom panel) Original images of heart slices from one control and one PTHrP(1-36)-treated pig. Heart slices are stained with triphenyltetrazolium chloride; using this method, regions of necrotic myocardium (highlighted by gray arrows) remain unstained and appear pale.