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Pharmacology: Medical And Biological Research

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Question:

Discuss about the Pharmacology for Medical and Biological Research.

 

Answer:

Responsible for Ang II generation

Angiotensin-converting enzyme (ACE) generates the production of Angiotensin II (Ang II) that mediates the renin-angiotensin-system (RAS) effects in the body (Becari et al., 2011). On the other hand, Elastase-2 (ELA-2) which is a chymotrypsin-serine protease elastase family member 2A alternatively generates the production of Ang II in the arteries of rats. RAS activation is accelerated after myocardial infarction, however the mechanisms are unknown that lead to Ang II generaton in resistance arteries (Ahmad et al., 2011). Therefore, the paper by Becari et al., (2017) deals with the study of Elastase-2 (ELA-2) activity contributing to increased Angiotensin II (Ang II) formation in resistant arteries and modulation of cardiac function after myocardial infarction (MI). They hypothesized that ELA-2 is responsible for the generation of Ang II and leads to cardiac damage in mice and MI. The result studies showed the first evidence for the hypothesis that ELA-2 is responsible for the formation of Ang II in the resistance arteries that is modulated to cardiac function after MI. This illustrates that ELA-2 is responsible for the ACE-independent dysregulation of RAS.

Techniques used

 

Genotyping

The tail tissue genomic DNA was obtained and amplification of the target gene by Polymerase Chain Reaction (PCR). Myocardial infarction was induced by ventral midline skin incision. They were killed by Carbon dioxide (CO2) inhalation after 4 weeks of MI surgery.

Echocardiography

Fractional shortening and ejection fraction was calculated for the systolic function of left ventricle (LV).

Histology

Mesenteric arterial bed removal was done and heart was harvested to calculate the infarct size and heart sections were analysed by video microscopy software Leica Qwin.

Randomization, group size or blinding

Randomization was done to MI or sham surgery in groups; sham WT, ELA-2 KO and MI ELA-2 KO through six independent experiments and data was analysed.

Statistical analysis and normalization

Log transformation was done to analyse the Ang I and Ang II concentration effect curves and data was analysed through nonlinear regression. Maximum contractile and PD2 values were obtained and two-way ANOVA was done for the statistical analysis.

(Table 1- techniques used)

Results:

Echocardiographic analysis

The heart images showed that in WT animals, there was a significantly large LV diameter than ELA-2 KO mice during the events of diastole and systole (4.1 ± 0.03 vs. 3.7 ± 0.07 mm, P < 0.05, respectively).This reduction of LV diameter was not observed in infracted mice. The assessment of cardiac function showed that there was decrease in MI and in the ejection fraction in both the strains of infracted and ELA-KO mice. Sham-ELA-2 KO mice showed a lower stroke volume and cardiac output as compared to WT mice. There was decreased cardiac output and stroke volume in WT mice as compared to ELA-2 KO mice. Uehara et al., (2013) also studied that Ang II is activated by RAS as the final physiological product and strong vasopressor that promote tissue remodelling in heart. This mechanism for cardiovascular remodelling is not known that can be helpful in inhibiting the Ang II formation and for the prevention of cardiovascular remodelling (Groutas, Dou & Alliston, 2011).

 

ELA-2 is functional in resistance arteries of mice

To confirm the functional analysis of ELA-2 in resistance mice arteries, ELA-2 KP mice were induced by chymostatin and no responses were obtained. However, there was significant attenuation of Ang I-induced maximal response in sham-WT mice. There was a rightward-shift of the concentration curve of Ang I due to chymostatin induction. This data clearly illustrated that Ang II generation was induced by serine proteases in resistance mesenteric arteries of mice and in turn, ELA-2 is the major driving reason for the generation of Ang-II enzyme in the arteries.

ELA-2 contribution to Ang-I in mesenteric resistance arteries of mice to MI

To confirm the ELA-2 contribution to Ang-I, Ang II and Ang I concentration curves were subjected to MI or sham-surgery. The concentration response curve shifted to left of Ang I with maximum effect in WT mice mesenteric arteries. There was also significant increase in the concentration of Ang I in WT mice as compared sham-Wt mice. This data confirmed that MI is strongly associated with increased RAS activation. Therefore, this paper provided the first evidence for the ELA-2 responsible for Ang II increased activity in mesenteric resistance arteries upon MI.

Ang I conversion to Ang II by ACE subjected to MI

There was rightward-shift in Ang I concentration response curves of mesenteric arteries when subjected Captopril. In ELA-2 KO mice, there was ACE-independent dysregulation of RAS in MI and it might be in other cardiovascular diseases. There is RAS hyperactivity associated with heart failure and there was significant increase in the RAS expression levels due to MI including myocardium (Santos et al., 2013). In a study conducted by Becari, Oliveira & Salgado, (2011) showed that cardiac changes in infracted mice was similar to humans that highlights the importance of ELA-2 as the driving factor for Ang I generation at an increased level.

The significance of the study is that the mechanism through which Ang II is converted from Ang I and synthesized in human tissues can be helpful in the pharmacology in inhibiting local Ang II formation and further MI (Thatcher et al., 2014). Therefore, this elucidation of ELA-2 being the contributor to the Ang II formation can be a great strategy for the prevention of cardiovascular diseases and remodelling as in MI.

From the above-obtained results, it can be inferred that ELA-2 is the contributor to vascular Ang II increased formation. It may also contribute to the cardiac dysfunctioning after MI. This implies that ELA-2 enzyme is the key player in the ACE-independent RAS dysregulation. This study confirmed that there is increased RAS activation in vascular beds as there was augmented Ang-1 induction in resistance arteries of sham-mice to MI. This is the first evidence provided by this study where MI did not affect the Ang I contractile responses that increased the generation of Ang-II upon MI. There is also significant cardiac sympathovagal balance dysregulation in ELA-2 KO mice along with increased parasympathetic and decreased sympathetic modulation. There was low cardiac output, heart rate, reduced LV and stroke volume that are interesting findings of this study adding to the existing knowledge of overall systemic or autonomic dysregulation in mesenteric nerves. This data indicated that ELA-2 plays the pivotal role in the peripheral resistance and basal cardiac function.

 

References

Ahmad, S., Simmons, T., Varagic, J., Moniwa, N., Chappell, M. C., & Ferrario, C. M. (2011). Chymase-dependent generation of angiotensin II from angiotensin-(1-12) in human atrial tissue. PloS one, 6(12), e28501.

Becari, C., Oliveira, E. B., & Salgado, M. C. O. (2011). Alternative pathways for angiotensin II generation in the cardiovascular system. Brazilian Journal of Medical and Biological Research, 44(9), 914-919.

Becari, C., Silva, M. A., Durand, M. T., Prado, C. M., Oliveira, E. B., Ribeiro, M. S., ... & Tostes, R. C. (2017). Elastase?2, an angiotensin II?generating enzyme, contributes to increased angiotensin II in resistance arteries of mice with myocardial infarction. British Journal of Pharmacology, 174(10), 1104-1115.

Becari, C., Teixeira, F. R., Oliveira, E. B., & Salgado, M. C. O. (2011). Angiotensin-converting enzyme inhibition augments the expression of rat elastase-2, an angiotensin II-forming enzyme. American Journal of Physiology-Heart and Circulatory Physiology, 301(2), H565-H570.

Groutas, W. C., Dou, D., & Alliston, K. R. (2011). Neutrophil elastase inhibitors. Expert opinion on therapeutic patents, 21(3), 339-354.

Santos, R. A., Ferreira, A. J., Verano-Braga, T., & Bader, M. (2013). Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: new players of the renin–angiotensin system. Journal of Endocrinology, 216(2), R1-R17.

Thatcher, S. E., Zhang, X., Howatt, D. A., Yiannikouris, F., Gurley, S. B., Ennis, T., ... & Cassis, L. A. (2014). Angiotensin-Converting Enzyme 2 Decreases Formation and Severity of Angiotensin II–Induced Abdominal Aortic Aneurysms. Arteriosclerosis, thrombosis, and vascular biology, ATVBAHA-114.

Uehara, Y., Miura, S. I., Yahiro, E., & Saku, K. (2013). Non-ACE pathway-induced angiotensin II production. Current pharmaceutical design, 19(17), 3054-3059.

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