Introduction: Patients with chronic obstructive pulmonary disease (COPD) often develop cardiovascular disorders such as right ventricular hypertrophy (RVH) and pulmonary hypertension (PH). We hypothesized that the neutrophil chemoattractant proline-glycine-proline (PGP), generated by the stepwise proteolytic cleavage of collagen by matrix metalloproteinases and prolyl endopeptidase (PE), would be involved in ongoing PH pathogenesis.

Methods: Mice were administered with acetylated PGP (Ac-PGP) (250 µg/dose) intratracheally for 6 and 10 weeks or exposed to cigarette smoke for 6 weeks to evaluate lung inflammation and RVH. To further elucidate the impact of PGP on pulmonary vascular remodeling, the PE inhibitor benzyloxycarbony-proline-prolinal (ZPP) was intratracheally administered in a 6-week smoking model.

Results: In mice treated with Ac-PGP at 6 weeks and 10 weeks, there was increased right ventricular systolic pressures (RVSP) when compared to the control group. The average ratio of RV/(LV+S) also showed significant increase with Ac-PGP administration. Ac-PGP levels in the blood was significantly increased after 6 weeks of smoke exposure. Treating the mice with ZPP intratracheally prior to smoke exposure significantly decreased inflammation in the lungs and prevented mice from developing PH. Furthermore, nitrite and nitrate levels in blood were elevated after smoke exposure and the nitrite/nitrate ratio returned to baseline levels after ZPP treatment, suggesting reduced oxidative stress.

Conclusion:  These results demonstrate that Ac-PGP induced the development of PH and that targeting of PGP peptides in a smoke model affects the development of RVH and PH.