Intracellular angiotensin (1–7) increases the inward calcium current in cardiomyocytes. On the role of PKA activation

Mello, Walmor C. De

doi:10.1007/s11010-015-2449-4

Cited by 12 publications

(5 citation statements)

References 31 publications

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“…After 4 min of perfusion, Ang-(1-9) induced a significant increase in developed pressure with a concomitant elevation in dP/dt max , confirming a positive inotropic response to Ang-(1-9) (Figure 7). Since protein kinase A (PKA) has been previously reported to modulate calcium flux via the L type Ca 2+ channel following application of Ang-(1-7) (24), we used the inhibitor H-89, which did indeed abolish the response to Ang-(1-9), thus supporting a role for PKA in the positive inotropic effect of Ang-(1-9).…”

Section: Resultsmentioning

confidence: 81%

“…We demonstrated a direct inotropic effect of Ang-(1-9), mediated through increasing Ca 2+ transient amplitude leading to increased contraction, and possibly explained via increased L-type Ca 2+ influx paralleled by increased SR Ca 2+ content. Although a direct inotropic effect of Ang-(1-9) has not been reported previously, when Ang-(1-7) is applied intracellularly to cardiomyocytes, PKA is activated, leading to increased L-type Ca 2+ channel activity (24). Ang II is reported to increase Ca 2+ transient amplitude and intracellular Ang II is reported to increase Ca 2+ transient amplitude via modulating L-type Ca 2+ current and releasing SR Ca 2+ 43, 44.…”

Section: Discussionmentioning

confidence: 90%

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Gene Therapy With Angiotensin-(1-9) Preserves Left Ventricular Systolic Function After Myocardial Infarction

Fattah

Nather

McCarroll

et al. 2016

Journal of the American College of Cardiology

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BackgroundAngiotensin-(1-9) [Ang-(1-9)] is a novel peptide of the counter-regulatory axis of the renin-angiotensin-aldosterone system previously demonstrated to have therapeutic potential in hypertensive cardiomyopathy when administered via osmotic mini-pump. Here, we investigate whether gene transfer of Ang-(1-9) is cardioprotective in a murine model of myocardial infarction (MI).ObjectivesThe authors evaluated effects of Ang-(1-9) gene therapy on myocardial structural and functional remodeling post-infarction.MethodsC57BL/6 mice underwent permanent left anterior descending coronary artery ligation and cardiac function was assessed using echocardiography for 8 weeks followed by a terminal measurement of left ventricular pressure volume loops. Ang-(1-9) was delivered by adeno-associated viral vector via single tail vein injection immediately following induction of MI. Direct effects of Ang-(1-9) on cardiomyocyte excitation/contraction coupling and cardiac contraction were evaluated in isolated mouse and human cardiomyocytes and in an ex vivo Langendorff-perfused whole-heart model.ResultsGene delivery of Ang-(1-9) reduced sudden cardiac death post-MI. Pressure volume measurements revealed complete restoration of end-systolic pressure, ejection fraction, end-systolic volume, and the end-diastolic pressure volume relationship by Ang-(1-9) treatment. Stroke volume and cardiac output were significantly increased versus sham. Histological analysis revealed only mild effects on cardiac hypertrophy and fibrosis, but a significant increase in scar thickness. Direct assessment of Ang-(1-9) on isolated cardiomyocytes demonstrated a positive inotropic effect via increasing calcium transient amplitude and contractility. Ang-(1-9) increased contraction in the Langendorff model through a protein kinase A–dependent mechanism.ConclusionsOur novel findings showed that Ang-(1-9) gene therapy preserved left ventricular systolic function post-MI, restoring cardiac function. Furthermore, Ang-(1-9) directly affected cardiomyocyte calcium handling through a protein kinase A–dependent mechanism. These data emphasized Ang-(1-9) gene therapy as a potential new strategy in the context of MI.

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Section: Resultsmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 90%

Gene Therapy With Angiotensin-(1-9) Preserves Left Ventricular Systolic Function After Myocardial Infarction

Fattah

Nather

McCarroll

et al. 2016

Journal of the American College of Cardiology

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“…Past reports regarding the direct effects of Ang-(1–7) on intracellular Ca 2+ mobilization in HF myocytes are conflicting. (12;18;19) One previous study indicated that acute Ang-(1–7) treatment does not modulate intracellular Ca 2+ handling in normal wild-type cardiomyocytes. (12) Consistent with that work, in the current investigation, Ang-(1–7) failed to alter the [Ca 2+ ] iT in normal myocytes of SD rats.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the direct effect of Ang-(1–7) on intracellular Ca 2+ mobilization in myocytes is unclear, since previous studies provided conflicting findings. (12;18;19) Furthermore, the ever-emerging body of experimental evidence continues to support that an important subset of cardiovascular actions of Ang-(1–7) is related to its bradykinin (BK) potentiating activity and its facilitation of nitric oxide (NO) release. (6;8;12;20;21) It is reasonable to speculate that the effects of Ang-(1–7) on myocyte may via Ang-(1–7) receptors while be coupled with NO/BK-mediated mechanism.…”

Section: Introductionmentioning

confidence: 99%

Cellular basis of angiotensin-(1-7)-induced augmentation of left ventricular functional performance in heart failure

Zhang

Cheng

Zhou

et al. 2017

International Journal of Cardiology

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Background Angiotensin-(1–7) [Ang-(1–7)] exhibits cardiovascular effects opposite those of angiotensin II (Ang II), thus providing protection against heart disease. However, how Ang-(1–7) imparts cardioprotection is unclear, and its direct cardiac effects are controversial. Whether heart failure (HF) alters cardiac contractile responses to Ang-(1–7) remains undetermined. We tested the hypothesis that in HF, Ang-(1–7) may produce positive modulation on [Ca2+]i regulation, enhancing left ventricular (LV) and myocyte contraction and relaxation via Ang-(1–7) Mas receptor coupled with nitric oxide (NO)/bradykinin (BK)-mediated mechanism. Methods and Results We measured LV contractility changes after Ang-(1–7) (650 ng/kg, iv) and compared myocyte functional and [Ca2+]i transient ([Ca2+]iT) responses to Ang-(1–7) superfusion in 24 normal rats and 34 rats with isoproterenol-induced HF (3 months after 170 mg/kg, s.q. for 2 days). To assess the mechanisms of altered HF responses to Ang-(1–7), subsets of HF myocytes were pretreated to inhibit NO synthase (L-NAME), BK (HOE-140), and Mas receptor (A-779) followed with Ang-(1–7). In normal rats, Ang-(1–7) produced no significant changes in LV and myocyte function. In HF rats, Ang-(1–7) significantly augmented LV contractility and relaxation with increased EES (51%), but decreased τ compared to baseline. Ang-(1–7) also significantly increased myocyte contraction (dL/dtmax, 30%), relaxation (dR/dtmax, 41%), and [Ca2+]iT. L-NAME increased, HOE-140 decreased, and A-779 prevented HF myocyte contractile responses to Ang-(1–7). Conclusions In a rat model of HF, Ang-(1–7) increases [Ca2+]iT, and produces positive inotropic and lusitropic effects in the LV and myocytes. These effects are mediated by the Mas receptor and involve activation of NO/BK pathways.

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“…It was previously reported that Ang-(1–7) could stimulate protein kinase A (PKA) production via the activation of MasR, which was followed by an enhanced calcium current in the heart. This mechanism thought to regulate calcium homeostasis and improve heart contractility [ 39 ]. Furthermore, Xu et al reported that administration of Ang-(1–7) could reverse the LPS-induced reduction of α-myosin heavy chain (MHC) and β-MHC, and increase levels of S100 calcium binding protein A8 (S100A8) and S100A9 in the mouse left ventricle and finally ameliorate ventricular contractility [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Diminazene aceturate mitigates cardiomyopathy by interfering with renin-angiotensin system in a septic rat model

Wang

et al. 2022

BMC Pharmacol Toxicol

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Background There were limited studies investigating treatments of septic cardiomyopathy (SCM), which is a common complication during sepsis. A septic rat model created by cecal ligation and puncture (CLP) was used to investigate the effects of diminazene aceturate (DIZE) in SCM. Methods A total of 151 Wistar rats were randomly assigned into the sham, CLP, or CLP + DIZE group. Data evaluated postoperatively at 6, 12, 24, and 48 hours included: cardiac function; plasma concentrations of tumor necrosis factor-alpha (TNF-α), interleukin-6, angiotensin-(1–7) [Ang-(1–7)], angiotensin II (AngII), troponin I, and brain natriuretic peptide; expression levels of myocardial Ang-(1–7), angiotensin-converting enzyme (ACE), ACE2, and angiotensin type 1 and Mas receptors; and histological changes. Results We found that the CLP + DIZE group had a lower mortality compared to the CLP group (38.5% versus 61.5%) within 48 h postoperatively, although without statistical significance. In contrast to the sham group, the CLP group had decreased cardiac functions, increased myocardial injuries, and higher TNF-α levels, which were ameliorated in the CLP + DIZE group. Furthermore, administration of DIZE could reverse the decreases of myocardial Ang-(1–7) and ACE2 expressions in the CLP group, which finally minimized the myocardial microstructure disruptions. Conclusions It was concluded that DIZE could mitigate the development of SCM and preserve cardiac function during sepsis possibly by interfering with the renin-angiotensin system through promoting myocardial ACE2 expression and restoring local Ang-(1–7) levels.

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Intracellular angiotensin (1–7) increases the inward calcium current in cardiomyocytes. On the role of PKA activation

Cited by 12 publications

References 31 publications

Gene Therapy With Angiotensin-(1-9) Preserves Left Ventricular Systolic Function After Myocardial Infarction

Gene Therapy With Angiotensin-(1-9) Preserves Left Ventricular Systolic Function After Myocardial Infarction

Cellular basis of angiotensin-(1-7)-induced augmentation of left ventricular functional performance in heart failure

Diminazene aceturate mitigates cardiomyopathy by interfering with renin-angiotensin system in a septic rat model

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