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. 2012;29(5-6):841-50.
doi: 10.1159/000178526. Epub 2012 May 11.

Direct renin inhibition exerts an anti-hypertrophic effect associated with improved mitochondrial function in post-infarction heart failure in diabetic rats

Rebecca Parodi-Rullan  1 , Giselle Barreto-Torres, Louis Ruiz, José Casasnovas, Sabzali Javadov
Affiliations

Direct renin inhibition exerts an anti-hypertrophic effect associated with improved mitochondrial function in post-infarction heart failure in diabetic rats

Rebecca Parodi-Rullan et al. Cell Physiol Biochem. 2012.

Abstract

Background: In addition to hypertension control, direct renin inhibition has been shown to exert direct beneficial effects on the heart in post-infarction cardiac remodeling. This study elucidates the possible contribution of mitochondria to the anti-hypertrophic effects of the direct renin inhibitor aliskiren in post-infarction heart failure complicated with diabetes in rats.

Methods: Diabetes was induced in male Sprague-Dawley rats by a single injection of streptozotocin (IP, 65 mg/kg body weight). After 7 days, the animals were randomly assigned to 4 groups: sham, heart failure, sham+aliskiren, and heart failure+aliskiren. Post-infarction HF was induced by coronary artery ligation for 4 weeks.

Results: showed that heart failure reduced ejection fraction and cardiac output by 41% (P<0.01) and 42% (P<0.05), respectively, compared to sham-operated hearts. Cardiac dysfunction was associated with suppressed state 3 respiration rates and respiratory control index in mitochondria, and increased mitochondrial permeability transition pore (PTP) opening. In addition, heart failure reduced expression of the major mitochondrial sirtuin, SIRT3 and increased acetylation of cyclophilin D, a regulatory component of the PTP. Aliskiren significantly improved cardiac function and abrogated mitochondrial perturbations.

Conclusion: Our results demonstrate that aliskiren attenuates post-infarction remodeling which is associated with its beneficial effects on mitochondria.

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Figures

Fig. 1
Fig. 1
Experimental design. Sham surgery or CAL were performed in rats one week after experimental diabetes (blood glucose: >15 mM) had been induced by streptozotocin. Experimental groups: Sham: hearts subjected to sham surgery; HF: hearts subjected to CAL; Sham+Als: hearts subjected to sham surgery and were treated with aliskiren (Als); CAL+Als: hearts subjected to CAL and were treated with Als.
Fig. 2
Fig. 2
Blood glucose levels (A), heart-to-body weight ratio (HW/BW, B) and expression of atrial natriuretic peptide (ANP, C) in sham-operated and post-infarcted hearts treated with or without aliskiren (Als). ANP gene expressions were normalized to ribosomal protein S11 (RPS11) mRNA. *P<0.05 HF vs. Sham.
Fig. 3
Fig. 3
Protein expression of angiotensin II type 1 (AT1R, A) and type 2 (AT2R, B) receptors in sham-operated and post-infarcted hearts treated with or without aliskiren (Als), and in Percoll-purified mitochondria isolated from control hearts (C). Homogenate (A, B) and mitochondrial (C) samples were resolved by SDS-PAGE and immunoblotted with AT1R or AT2R antibodies. Actin and GAPDH were used as the housekeeping proteins for cytosol whereas COXIV expression is shown as a mitochondrial marker. *P<0.05 HF+Als vs. HF.
Fig. 4
Fig. 4
The effect of aliskiren (Als) on cardiac output (CO, A), ejection fraction (EF%, B) and left ventricle (LV) fractional shortening (FS%, C) of hearts 28 days after sham-procedure or CAL. Calculations of functional parameters of the heart are given in Materials and Methods. *P<0.05 and **P<0.01 HF vs. Sham; +P<0.05 HF+Als vs. HF.
Fig. 5
Fig. 5
The effect of aliskiren (Als) on state 3 respiration rate (A), respiratory control index (RCI, B), cytochrome c-stimulated respiration (C) and citrate synthase activity (D) of mitochondria isolated from sham-operated and post-infarcted hearts treated with or without aliskiren (Als). Cytochrome c (cyt c, 20 μM) was added directly to the cuvette to measure cytochrome c stimulation of respiration with complex I substrates in the presence of 1 mM ADP (state 3). Data are shown as mean ± SEM of 10-12 hearts in each group. *P<0.05 and **P<0.01 HF vs. Sham; +P<0.05 HF+Als vs. HF.
Fig. 6
Fig. 6
Rate of Ca2+-induced swelling as an indicator of PTP opening in mitochondria isolated from sham-operated or post-infarction hearts treated with aliskiren (Als). Measurement of the PTP under de-energized conditions was performed by monitoring the calcium-induced decrease in light scattering (A520). (A) Original traces are shown for one mitochondrial preparation derived from hearts of sham, HF, sham+Als or HF+Als groups. Additionally, mitochondria isolated from hearts of HF group were treated in vitro with 10 μM Als (HF+Als in vitro) or 0.6 μM sanglifehrin A (HF+SfA in vitro). To measure the effect of Als or SfA on PTP opening in vitro, the inhibitors were added directly to the cuvette and swelling of mitochondria was monitored. Matrix swelling was induced by 200 μM Ca2+. Maximal swelling was induced by 1 mM Ca2+. (B) Rate of swelling of mitochondria. Data are expressed relative to the maximum rate determined at 1 mM Ca2+ and were determined by differentiation of the traces shown to obtain the maximum rate of change of A520. *P<0.05 shows the level of significance between the compared groups.
Fig. 7
Fig. 7
The effects of post-infarction HF on mitochondrial total protein, CyP-D acetylation, and sirtuin levels. (A, B,C) Mitochondrial proteins were resolved by SDS-PAGE and probed with anti-acetylated lysine (Ac-Lys), SIRT3, SIRT4 or SIRT5 antibodies. The same membranes were stripped and reprobed with COXIV as a housekeeping protein for mitochondria. (D) Immunoprecipitation (IP) of mitochondrial proteins with Ac-Lys followed by immunoblotting (IB) for CyP-D and ANT was performed to assay CyP-D acetylation. In addition, IP was performed with CyP-D and ANT antibodies as controls.
Fig. 8
Fig. 8
Proposed mechanism of the mitochondria-mediated anti-remodeling effect of aliskiren in post-infarction heart failure.
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