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Rapamycin Attenuates Cardiac Expression of Anti‐inflammatory AT2R and Anti‐Apoptotic MCL1
Author(s) -
Arnold Nicholas,
Somashekara Divyashree,
Gul Rukhsana,
Speth Robert,
Pulakat Lakshmidevi
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.835.13
Subject(s) - angiotensin ii , chemistry , downregulation and upregulation , apoptosis , receptor , pharmacology , inflammation , mcl1 , renin–angiotensin system , endocrinology , medicine , gene , biochemistry , blood pressure
Angiotensin II (Ang II) receptor AT2R is a member of the vasodilative/anti‐inflammatory branch of renin‐angiotensin system (RAS). However, mechanisms underlying regulation of AT2R expression in cardiomyocytes are not understood. To determine how vasodilative insulin (INS) and anti‐inflammatory drug rapamycin (Rap) modulate AT2R expression, we performed radioligand binding experiments with 125 I‐CGP42112A, an AT2 specific ligand, on mouse atrial cardiomyocyte HL‐1 cells. INS (100nM, 12h) increased expression of functional AT2R that binds 125 I‐CGP42112A by 2.2 fold (P<0.05). Co‐treatment with Rap (10nM) attenuated this effect. Our in silico and in vitro studies showed that the AT2R is a target for the diabetic marker microRNA miR‐29 family. Expression levels of miR‐29a, b and c in HL‐1 cells were suppressed by INS and elevated by Rap (~3 fold; P<0.05). Moreover, transfection of HL‐1 cells with miR‐29 mimics reduced 125 I‐CGP42112A binding and suppressed insulin‐induced increases in AT2R protein (P<0.05). Immunoblotting showed that Rap also suppressed miR‐29 target Mcl‐1, an anti‐apoptotic gene that promotes cardiomyocyte survival following ischemia‐reperfusion. Collectively these data show for the first time that Rap, a widely used anti‐inflammatory drug, attenuates cardiac expression of AT2R and Mcl1 and up‐regulates miR‐29 family that may promote cardiac INS resistance.