Abstract Body: During hypertensive crises (BP >180/120 mm Hg), turbulent passage of red blood cells through severely constricted blood vessels can cause blood cell fragmentation and intravascular hemolysis. Consistent with this, in mice we found that a rapid and large increase in BP (by ~60-70 mm Hg) induced by an Ang II-infusion (0.2 ug/g BW) resulted in hemolysis. Prolyl Endo-Peptidase (PEP) is an intracellular enzyme that converts Ang II to Ang-(1-7), thereby shifting from a powerful vasopressor peptide to a counter regulatory peptide. The Ang II-induced acute BP increase that caused a visible hemolysis was associated with a ~4-fold increase in PEP activity (Figure, Panel A). A massive hemolysis induced by freeze-thawing of blood (cryo-hemolysis), moreover, was associated with a ~20x increase in PEP activity as compared to native plasma (Panel B). Of note, mouse cryo-hemolyzed plasma (HP) ex vivo was able to produce substantially more Ang-(1-7) peptide from spiked Ang II than equivalent amount of non-hemolyzed plasma (P). In addition, when PEP inhibitor, S-17092, was added to cryo-hemolyzed plasma (HP inh), Ang-(1-7) formation from Ang II was greatly diminished (Panel C). This suggests that blood corpuscles acting via intracellular PEP are endowed with a larger capacity than native plasma to catabolize the vasoconstrictor peptide Ang II to the vasodilator peptide Ang-(1-7).
In conclusion, a large and rapid increase in BP after Ang II infusion causes hemolysis which is associated with the release of intracellular PEP enzyme from blood cells. We propose that the release of PEP confers a protective mechanism against severe BP elevations during hypertensive crisis by granting higher plasma Ang II-degrading capability thereby lowering Ang II and BP. This occurs at the expense of temporary hemolysis in the setting of hypertensive crisis as seen with malignant hypertension.