Cardiac Angiotensin II Is Generated Locally by ACE and Not Chymase

Chymase in Plasma and Urine Extracellular Vesicles: Novel Biomarkers for Primary Hypertension

“…The pathogenic importance of chymase as contributing to cardiovascular pathology remains controversial, in part because its primary intracellular location has been equivocally interpreted to exclude the enzyme from contact with interstitial or circulating angiotensinogen or angiotensin I 23,50 . While Danser and colleagues 23,51 persist in dismissing chymase as a contributor to tissue Ang II formation and cardio-renal dysfunction, the data reported here provides a novel mechanism by which chymase, residing in the protected environment of EV, could transport the enzyme to cells in cardiovascular tissues. Transferring proteins and lipids locally and systemically to other organs is a fundamental function of EVs 35 .…”

“…A heightened renin angiotensin system (RAS) activity in human hypertension is acknowledged and consistent with the beneficial action of angiotensin converting enzyme (ACE) inhibitors and angiotensin II (Ang II) receptor blockers (ARBs) in blood pressure control and halting or reversing adverse cardiovascular remodeling 12 . Although multiple factors contribute to suboptimal control of human hypertension and its cardiovascular sequela, increased attention to compensatory activation of alternate enzymatic pathways for Ang II-induced pathology following RAS pharmacotherapy is resurfacing 13,14 (1-12)] as an alternate tissue forming Ang II substrate by chymase has provided an experimental basis for targeting non-renin and ACE-independent mechanisms for hypertension [15][16][17][18][19] .…”

“…A vexing problem in accepting the criticality of chymase as a primary cardiac and tissue Ang II forming enzyme is that the intracellular location of the enzyme prevents it from accessing circulating or extracellularly present angiotensin I (Ang I) 23,24 . This issue has led some investigators to exclude chymase as a tissue-residing mechanism for the catalytic conversion of Ang I into Ang II 23,25,26 .…”

“…A vexing problem in accepting the criticality of chymase as a primary cardiac and tissue Ang II forming enzyme is that the intracellular location of the enzyme prevents it from accessing circulating or extracellularly present angiotensin I (Ang I) 23,24 . This issue has led some investigators to exclude chymase as a tissue-residing mechanism for the catalytic conversion of Ang I into Ang II 23,25,26 . This equivocal interpretation of RAS biotransformation mechanisms may be put to rest by our finding of chymase uptake by rat cardiomyocytes 24 h after intravenous injection of EVs isolated from the pericardial fluid of patients undergoing cardiac surgery 27 .…”