Abstract
In vitro and ex vivo experiments indicate that elastase-2 (ELA-2), a chymotrypsin-serine protease elastase family member 2A, is an alternative pathway for angiotensin II (Ang II) generation. However, the role played by ELA-2 in vivo is unclear. We examined ELA-2 knockout (ELA-2KO) mice compared to wild-type (WT) mice and determined whether ELA-2 played a role in hemodynamics [arterial pressure (AP) and heart rate (HR)], cardiocirculatory sympathovagal balance and baroreflex sensitivity. The variability of systolic arterial pressure (SAP) and pulse interval (PI) for evaluating autonomic modulation was examined for time and frequency domains (spectral analysis), whereas a symbolic analysis was also used to evaluate PI variability. In addition, baroreflex sensitivity was examined using the sequence method. Cardiac function was evaluated echocardiographically under anesthesia. The AP was normal whereas the HR was reduced in ELA-2KO mice (425 ± 17 vs. 512 ± 13 bpm from WT). SAP variability and baroreflex sensitivity were similar in both strains. The LF power from the PI spectrum (33.6 ± 5 vs. 51.8 ± 4.8 nu from WT) and the LF/HF ratio (0.60 ± 0.1 vs. 1.45 ± 0.3 from WT) were reduced, whereas the HF power was increased (66.4 ± 5 vs. 48.2 ± 4.8 nu from WT) in ELA-2KO mice, indicating a shift toward parasympathetic modulation of HR. Echocardiographic examination showed normal fractional shortening and an ejection fraction in ELA-2KO mice; however, the cardiac output, stroke volume, and ventricular size were reduced. These findings provide the first evidence that ELA-2 acts on the sympathovagal balance of the heart, as expressed by the reduced sympathetic modulation of HR in ELA-2KO mice.
Highlights
The beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in the treatment of arterial hypertension, congestive heart failure, and other cardiovascular diseases are well documented (Hansson et al, 1999; Jorde et al, 2000; Yusuf et al, 2000; Lindholm et al, 2002; Jandeleit-Dahm et al, 2005; Feldstein, 2014; Te Riet et al, 2015)
ELA-2 knockout (ELA-2KO) mice showed a lower basal heart rate compared to WT mice (Figure 1B), whereas there was no difference in the basal mean arterial pressure (Figure 1A)
The systolic arterial pressure (SAP) variability, SAP (Figure 3A) and low frequency (LF) band (Figure 3B) were not different in ELA-2KO mice compared to WT mice
Summary
The beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in the treatment of arterial hypertension, congestive heart failure, and other cardiovascular diseases are well documented (Hansson et al, 1999; Jorde et al, 2000; Yusuf et al, 2000; Lindholm et al, 2002; Jandeleit-Dahm et al, 2005; Feldstein, 2014; Te Riet et al, 2015). Elastase-2 (ELA-2), a chymotrypsin-serine protease elastase family member 2A, is an alternative Ang II generator. This enzyme is widely distributed in several murine organs, such as the lung, pancreas, liver, heart, kidney, and blood vessels (Santos et al, 2002; Becari et al, 2011). The functional role of ELA-2 for Ang II generation was demonstrated in both in vitro and ex vivo mesenteric arterial beds (Santos et al, 2002, 2003), hearts and carotid arteries (Becari et al, 2005, 2011). The in vivo role of ELA-2 remains unclear, and there are no reports providing support for its participation in cardiocirculatory regulation under physiological conditions. To investigate whether ELA -2 plays a role in cardiocirculatory regulation, our laboratory developed a knockout mouse strain for the ELA-2 gene (ELA-2KO)
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