Effects of triiodo-thyronine on angiotensin- induced cardiomyocyte hypertrophy: reversal of increased b-myosin heavy chain gene expression Baohua Wang, Jingping Ouyang, and Zhengyuan Xia Abstract: Thyroid hormone-induced cardiac hypertrophy is similar to that observed in physiological hypertrophy, which is associated with high cardiac contractility and increased a-myosin heavy chain (a-MHC, the high ATPase activity isoform) expression. In contrast, angiotensin II (Ang II) induces an increase in myocardial mass with a compromised contractility accompanied by a shift from a-MHC to the fetal isoform b-MHC (the low ATPase activity isoform), which is considered as a pathological hypertrophy and inevitably leads to the development of heart failure. The present study is designed to as- sess the effect of thyroid hormone on angiotensin II-induced hypertrophic growth of cardiomyocytes in vitro. Cardiomyo- cytes were prepared from hearts of neonatal Wistar rats. The effects of Ang II and 3,3’,5-triiodo-thyronine (T 3 ) on incorporations of [ 3 H]-thymine and [ 3 H]-leucine, MHC isoform mRNA expression, PKC activity, and PKC isoform protein expression were studied. Ang II enhanced [ 3 H]-leucine incorporation, b-MHC mRNA expression, PKC activity, and PKCe expression and inhibited a-MHC mRNA expression in cardiomyocytes. T3 treatment prevented Ang II-induced increases in PKC activity, PKCe, and b-MHC mRNA overexpression and favored a-MHC mRNA expression. Thyroid hormone ap- pears to be able to reprogram gene expression in Ang II-induced cardiac hypertrophy, and a PKC signal pathway may be involved in such remodeling process. Key words: angiotensin II, cardiomyocytes, myosin heavy chain, protein kinase C, thyroid hormone. Re ´sume ´: L’hypertrophie cardiaque induite par l’hormone thyroı ¨dienne est similaire a ` l’hypertrophie physiologique qui est associe ´e a ` une forte contractilite ´ cardiaque et a ` une augmentation de l’expression de la chaı ˆne lourde de l’alpha myosine (a-MHC, isoforme a ` forte activite ´ ATPase). A ` l’oppose ´, l’angiotensine II (Ang II) induit une augmentation de la masse myocardique avec une contractilite ´ affaiblie accompagne ´e d’un de ´placement de l’a-MHC vers l’isoforme b-MHC (iso- forme a ` faible activite ´ ATPase), qui est conside ´re ´e comme une hypertrophie pathologique et conduit ine ´vitablement au de ´- veloppement de l’insuffisance cardiaque. La pre ´sente e ´tude a pour but d’e ´valuer l’effet de l’hormone thyroı ¨dienne sur l’hypertrophie des cardiomyocytes in vitro induite par l’angiotensine II. On a pre ´pare ´ des cardiomyocytes provenant de cœurs de rats Wistar ne ´onatals. On a examine ´ les effets de l’Ang II et de 3,3’,5-triiodo-thyronine (T 3 ) sur l’incorporation de [ 3 H]thymine et de [ 3 H]-leucine, l’expression de l’ARNm de l’isoforme MHC, l’activite ´ de la prote ´ine kinase C (PKC) et l’expression de la prote ´ine de l’isoforme PKC. L’Ang II a stimule ´ l’incorporation de [ 3 H]-leucine, l’expression de l’ARNm de l’isoforme b-MHC, l’activite ´ PKC et l’expression de la PKCe, et inhibe ´ l’expression de l’ARNm de l’iso- forme a-MHC dans les cardiomyocytes. Le traitement a ` la T 3 a pre ´venu les augmentations induites par Ang II de l’ac- tivite ´ de la PKC ainsi que la surexpression de l’ARNm de la b-MHC et de la PKCe, et facilite ´ l’expression de l’ARNm de l’a-MHC. Il semble que l’hormone thyroı ¨dienne soit capable de reprogrammer l’expression ge ´nique dans l’hypertrophie cardiaque induite par l’Ang-II, et la voie des signaux PKC pourrait jouer un ro ˆle dans ce processus de remodelage. Mots cle ´s : angiotensine II, cardiomyocytes, chaı ˆne lourde de la myosine, prote ´ine kinase C, hormone thyroı ¨dienne. [Traduit par la Re ´daction] Introduction Cardiac hypertrophy is an adaptive process of postmitotic cardiomyocytes in response to various stresses including he- modynamic overload and neurohumoral stimuli. It is one of the most important risk factors in many cardiac diseases. Pathological hypertrophy compromises cardiac contractility and could lead the development of heart failure (Dorn and Force 2005). Increased cardiomyocyte size and protein syn- thesis are the primary characteristics of cardiomyocytes in over-growth myocardium. In general, cardiomyocytes lose the ability to synthesize DNA soon after birth; they only in- crease in size but not cell number in response to growth stimuli. Together with acceleration in the synthesis of gen- eral cellular protein, the changes in gene programming char- acterized by the induction of a specific set of fetal contractile protein gene expression such as b-myosin heavy chain (b-MHC) and a-skeletal actin have been recognized as Received 30 August 2005. Published on the NRC Research Press Web site at http://cjpp.nrc.ca on 31 October 2006. B. Wang and J. Ouyang. Department of Pathophysiology, School of Medicine, Wuhan University, Wuhan, 430071, P.R. China. Z. Xia. 1 Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. 1 Corresponding author (e-mail: zhengyuan_xia@yahoo.com). 935 Can. J. Physiol. Pharmacol. 84: 935–941 (2006) doi:10.1139/Y06-043 # 2006 NRC Canada