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Angiotensin-(1-12)/chymase axis modulates cardiomyocyte L-type calcium currents in rats expressing human angiotensinogen.

Abstract

BACKGROUND

Activation of the intracrine renin angiotensin systems (RAS) is increasingly recognized as contributing to human pathologies, yet non-canonical renin-independent mechanisms for angiotensin II (Ang II) biosynthesis remain controversial. Direct Ang II generation from angiotensin-(1-12) [Ang-(1-12)] by chymase is an essential intracrine source for regulation of cardiac function. Using a transgenic rat model that overexpresses the human angiotensinogen gene [TGR(hAGT)L1623] and displays increased cardiac Ang II levels, this study aimed to provide evidence for intracrine activation of L-type calcium currents (ICa-L) mediated by the Ang-(1-12)/chymase axis.

METHODS AND RESULTS

On patch clamp, ICa-L density was significantly higher in TGR(hAGT)L1623 (-6.4 ± 0.3 pA/pF) compared to Sprague Dawley (SD) cardiomyocytes (-4.8, ± 0.5 pA/pF). Intracellular administration of Ang II and Ang-(1-12) elicited a ICa-L increase in both SD and TGR(hAGT)L1623 cardiomyocytes, albeit blunted in transgenic cells. ICa-L activation by intracellular Ang II and Ang-(1-12) was abolished by the specific Ang II type 1 receptor blocker E-3174. Co-administration of a chymase inhibitor prevented activation of ICa-L by Ang-(1-12). Confocal micrographs revealed abundant chymase (mast cell protease 5) immunoreactive protein in SD and TGR(hAGT)L1623 cardiomyocytes.

CONCLUSIONS

Our data demonstrate the existence in cardiomyocytes of a calcium channel modulatory activity responsive to Ang II generated by the Ang-(1-12)/chymase axis that signals via intracellular receptors. Chronically elevated Ang II in TGR(hAGT)L1623 hearts leading to increased intracellular calcium through ICa-L suggests that activation of this Ang-(1-12)/chymase-governed cardiac intracrine RAS may contribute to the pathological phenotypes observed in the humanized model of chronic hypertension and cardiac hypertrophy.

Authors+Show Affiliations

Department of Surgery, Wake Forest School of Medicine, Winston-Salem, NC, USA. Electronic address: bmsarey@gmail.com.Department of Internal Medicine, Section on Cardiovascular Medicine, Wake Forest School of Medicine, Winston Salem, NC, USA.Department of Surgery, Wake Forest School of Medicine, Winston-Salem, NC, USA.Department of Surgery, Wake Forest School of Medicine, Winston-Salem, NC, USA.Department of Surgery, Wake Forest School of Medicine, Winston-Salem, NC, USA.Department of Surgery, Wake Forest School of Medicine, Winston-Salem, NC, USA.Department of Surgery, Wake Forest School of Medicine, Winston-Salem, NC, USA.Birmingham Veteran Affairs Medical Center and Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL, USA.Department of Surgery and Cardiovascular Sciences Center, Wake Forest School of Medicine, Winston-Salem, NC, USA.Departments of Surgery, Physiology and Pharmacology, and Social Sciences, Division of Public Health, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31629566

Citation

Reyes, Santiago, et al. "Angiotensin-(1-12)/chymase Axis Modulates Cardiomyocyte L-type Calcium Currents in Rats Expressing Human Angiotensinogen." International Journal of Cardiology, 2019.
Reyes S, Cheng CP, Roberts DJ, et al. Angiotensin-(1-12)/chymase axis modulates cardiomyocyte L-type calcium currents in rats expressing human angiotensinogen. Int J Cardiol. 2019.
Reyes, S., Cheng, C. P., Roberts, D. J., Yamashita, T., Ahmad, S., VonCannon, J. L., ... Ferrario, C. M. (2019). Angiotensin-(1-12)/chymase axis modulates cardiomyocyte L-type calcium currents in rats expressing human angiotensinogen. International Journal of Cardiology, doi:10.1016/j.ijcard.2019.09.052.
Reyes S, et al. Angiotensin-(1-12)/chymase Axis Modulates Cardiomyocyte L-type Calcium Currents in Rats Expressing Human Angiotensinogen. Int J Cardiol. 2019 Oct 8; PubMed PMID: 31629566.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Angiotensin-(1-12)/chymase axis modulates cardiomyocyte L-type calcium currents in rats expressing human angiotensinogen. AU - Reyes,Santiago, AU - Cheng,Che Ping, AU - Roberts,Drew J, AU - Yamashita,Tomohisa, AU - Ahmad,Sarfaraz, AU - VonCannon,Jessica L, AU - Wright,Kendra N, AU - Dell'Italia,Louis J, AU - Varagic,Jasmina, AU - Ferrario,Carlos M, Y1 - 2019/10/08/ PY - 2019/06/18/received PY - 2019/09/18/revised PY - 2019/09/24/accepted PY - 2019/10/21/entrez PY - 2019/10/21/pubmed PY - 2019/10/21/medline KW - Ang II KW - Ang-(1–12) KW - Angiotensin II type 1 receptor KW - Chymase KW - Hypertension KW - Hypertrophy JF - International journal of cardiology JO - Int. J. Cardiol. N2 - BACKGROUND: Activation of the intracrine renin angiotensin systems (RAS) is increasingly recognized as contributing to human pathologies, yet non-canonical renin-independent mechanisms for angiotensin II (Ang II) biosynthesis remain controversial. Direct Ang II generation from angiotensin-(1-12) [Ang-(1-12)] by chymase is an essential intracrine source for regulation of cardiac function. Using a transgenic rat model that overexpresses the human angiotensinogen gene [TGR(hAGT)L1623] and displays increased cardiac Ang II levels, this study aimed to provide evidence for intracrine activation of L-type calcium currents (ICa-L) mediated by the Ang-(1-12)/chymase axis. METHODS AND RESULTS: On patch clamp, ICa-L density was significantly higher in TGR(hAGT)L1623 (-6.4 ± 0.3 pA/pF) compared to Sprague Dawley (SD) cardiomyocytes (-4.8, ± 0.5 pA/pF). Intracellular administration of Ang II and Ang-(1-12) elicited a ICa-L increase in both SD and TGR(hAGT)L1623 cardiomyocytes, albeit blunted in transgenic cells. ICa-L activation by intracellular Ang II and Ang-(1-12) was abolished by the specific Ang II type 1 receptor blocker E-3174. Co-administration of a chymase inhibitor prevented activation of ICa-L by Ang-(1-12). Confocal micrographs revealed abundant chymase (mast cell protease 5) immunoreactive protein in SD and TGR(hAGT)L1623 cardiomyocytes. CONCLUSIONS: Our data demonstrate the existence in cardiomyocytes of a calcium channel modulatory activity responsive to Ang II generated by the Ang-(1-12)/chymase axis that signals via intracellular receptors. Chronically elevated Ang II in TGR(hAGT)L1623 hearts leading to increased intracellular calcium through ICa-L suggests that activation of this Ang-(1-12)/chymase-governed cardiac intracrine RAS may contribute to the pathological phenotypes observed in the humanized model of chronic hypertension and cardiac hypertrophy. SN - 1874-1754 UR - https://www.unboundmedicine.com/medline/citation/31629566/Angiotensin-(1-12)/chymase_axis_modulates_cardiomyocyte_L-type_calcium_currents_in_rats_expressing_human_angiotensinogen L2 - https://linkinghub.elsevier.com/retrieve/pii/S0167-5273(19)33136-5 DB - PRIME DP - Unbound Medicine ER -