Aliskiren and Valsartan Reduce Myocardial AT1 Receptor Expression and Limit Myocardial Infarct Size in Diabetic Mice

Ye, Yumei; Qian, Jinqiao; Castillo, Alexander; Perez‐Polo, J. Regino; Birnbaum, Yochai

doi:10.1007/s10557-011-6339-z

Cited by 23 publications

(16 citation statements)

References 78 publications

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“…Animal studies also showed that treatment with losartan induced the tubular expression of SIRT1. In support of our results, it has been reported that treatment with other ARBs, such as telmisartan and valsartan, increased the expression of SIRT1 in skeletal muscle cells of obese db/db mice and in myocardial cells of type-2 diabetes mellitus mice, respectively [27,28]. In addition, we also found that the inhibitory effect of losartan on the ER stress was mediated through the up-regulation of SIRT1.…”

Section: Discussionsupporting

confidence: 91%

Anti-Fibrotic Effect of Losartan, an Angiotensin II Receptor Blocker, Is Mediated through Inhibition of ER Stress via Up-Regulation of SIRT1, Followed by Induction of HO-1 and Thioredoxin

Kim

Baek

Lee

et al. 2017

IJMS

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Endoplasmic reticulum (ER) stress is increasingly identified as modulator of fibrosis. Losartan, an angiotensin II receptor blocker, has been widely used as the first choice of treatment in chronic renal diseases. We postulated that anti-fibrotic effect of losartan is mediated through inhibition of ER stress via SIRT1 (silent mating type information regulation 2 homolog 1) hemeoxygenase-1 (HO-1)/thioredoxin pathway. Renal tubular cells, tunicamycin (TM)-induced ER stress, and unilateral ureteral obstruction (UUO) mouse model were used. Expression of ER stress was assessed by Western blot analysis and immunohistochemical stain. ER stress was induced by chemical ER stress inducer, tunicamycin, and non-chemical inducers such as TGF-β, angiotensin II, high glucose, and albumin. Losartan suppressed the TM-induced ER stress, as shown by inhibition of TM-induced expression of GRP78 (glucose related protein 78) and p-eIF2α (phosphospecific-eukaryotic translation initiation factor-2α), through up-regulation of SIRT1 via HO-1 and thioredoxin. Losartan also suppressed the ER stress by non-chemical inducers. In both animal models, losartan reduced the tubular expression of GRP78, which were abolished by pretreatment with sirtinol (SIRT1 inhibitor). Sirtinol also blocked the inhibitory effect of losartan on the UUO-induced renal fibrosis. These findings provide new insights into renoprotective effects of losartan and suggest that SIRT1, HO-1, and thioredoxin may be potential pharmacological targets in kidney diseases under excessive ER stress condition.

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Section: Discussionsupporting

confidence: 91%

Anti-Fibrotic Effect of Losartan, an Angiotensin II Receptor Blocker, Is Mediated through Inhibition of ER Stress via Up-Regulation of SIRT1, Followed by Induction of HO-1 and Thioredoxin

Kim

Baek

Lee

et al. 2017

IJMS

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“…Consequently, by applying oral doses that were over 10 times higher than those used in humans (62.5 mg/kg p.o. per day versus 150-300 mg/day in humans), we were able, as in previous studies [21,22], to achieve a degree of RAS blockade that yielded the same BP-lowering effects as losartan at 60 mg/ kg p.o. per day.…”

Section: Discussionsupporting

confidence: 75%

“…per day; a kind gift of Novartis Pharmaceuticals, Basel, Switzerland), or propranolol (50 mg/kg p.o. per day; Sigma, St. Louis, Missouri, USA) in drinking water, as described before [13,15,21,22].…”

Section: Treatmentmentioning

confidence: 99%

AT1-receptor blockade, but not renin inhibition, reduces aneurysm growth and cardiac failure in fibulin-4 mice

Riet

Deel

Thiel

et al. 2016

Journal of Hypertension

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“…Subcutaneous 0.1 mg/kg buprenorphine was administered, the chest was closed, and mice were allowed to recover from anesthesia. Twenty-four hours after reperfusion, mice were reanesthetized, the coronary artery was reoccluded, Evan's blue dye (3%) was injected into the right ventricle, and mice were euthanized under deep anesthesia (70).…”

Section: Ismentioning

confidence: 99%

“…Areas of the AAR and IS in each slice were determined by planimetry, converted into percentages of the whole for each slice, and multiplied by the weight of the slice. The results were summed to obtain the weight of the myocardial AAR and IS (70).…”

Section: Determination Of the Aar And Ismentioning

confidence: 99%

Phosphodiesterase-3 inhibition augments the myocardial infarct size-limiting effects of exenatide in mice with type 2 diabetes

Qian

Castillo

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Glucagon-like peptide (GLP)-1 receptor activation increases intracellular cAMP with downstream activation of PKA. Cilostazol (CIL), a phosphodiesterase-3 inhibitor, prevents cAMP degradation. We assessed whether CIL amplifies the exenatide (EX)-induced increase in myocardial cAMP levels and PKA activity and augments the infarct size (IS)-limiting effects of EX in db/db mice. Mice fed a Western diet received oral CIL (10 mg/kg) or vehicle by oral gavage 24 h before surgery. One hour before surgery, mice received EX (1 μg/kg sc) or vehicle. Additional mice received H-89, a PKA inhibitor, alone or with CIL + EX. Mice underwent 30 min of coronary artery occlusion and 24 h of reperfusion. Both EX and CIL increased myocardial cAMP levels and PKA activity. Levels were significantly higher in the EX + CIL group. Both EX and CIL reduced IS. IS was the smallest in the CIL + EX group. H-89 completely blocked the IS-limiting effects of EX + CIL. EX + CIL decreased phosphatase and tensin homolog on chromosome 10 upregulation and increased Akt and ERK1/2 phosphorylation after ischemia-reperfusion. These effects were blocked by H-89. In conclusion, EX and CIL have additive effects on IS limitation in diabetic mice. The additive effects are related to cAMP-induced PKA activation, as H-89 blocked the protective effect of CIL + EX.

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Aliskiren and Valsartan Reduce Myocardial AT1 Receptor Expression and Limit Myocardial Infarct Size in Diabetic Mice

Cited by 23 publications

References 78 publications

Anti-Fibrotic Effect of Losartan, an Angiotensin II Receptor Blocker, Is Mediated through Inhibition of ER Stress via Up-Regulation of SIRT1, Followed by Induction of HO-1 and Thioredoxin

Anti-Fibrotic Effect of Losartan, an Angiotensin II Receptor Blocker, Is Mediated through Inhibition of ER Stress via Up-Regulation of SIRT1, Followed by Induction of HO-1 and Thioredoxin

AT1-receptor blockade, but not renin inhibition, reduces aneurysm growth and cardiac failure in fibulin-4 mice

Phosphodiesterase-3 inhibition augments the myocardial infarct size-limiting effects of exenatide in mice with type 2 diabetes

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