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(Circulation. 2004;109:2240-2245.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Thyrotropin-Releasing Hormone Is Induced in the Left Ventricle of Rats With Heart Failure and Can Provide Inotropic Support to the Failing Heart

Hongkui Jin, MD^*; Grazyna Fedorowicz, MS^*; Renhui Yang, MD; Annie Ogasawara, BS; Franklin Peale, MD, PhD; Thinh Pham, BS; Nicholas F. Paoni, PhD

From Genentech, Inc, South San Francisco, Calif. Dr Paoni is now at the Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Ind.

Correspondence to Hongkui Jin, MD, Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080. E-mail hkj{at}gene.com

Received November 24, 2003; revision received January 27, 2004; accepted February 2, 2004.

Background— We reported previously that left ventricular gene expression for thyrotropin-releasing hormone (TRH) precursor was increased in rats with heart failure 8 weeks after myocardial infarction (MI) and that early ACE inhibition tended to cause further myocardial induction of this gene.

Methods and Results— Here, we show that after MI, the expression of pro-TRH is induced in the heart coordinately with the protease PC1, an important enzyme in TRH biosynthesis. Pro-TRH gene expression was induced in cardiac interstitial cells after MI, and this effect was restricted to the heart, because no increase in TRH mRNA abundance was observed in the hypothalamus, kidney, or lung. Transcript abundance of pro-TRH can be increased in cultured cardiac fibroblasts by several adrenergic agonists, indicating that the adrenergic axis may play a regulatory role in cardiac TRH production. Acute intravenous administration of TRH to rats with ischemic cardiomyopathy caused a significant increase in heart rate, mean arterial pressure, cardiac output, stroke volume, and cardiac contractility.

Conclusions— Taken together, these results indicate that TRH is specifically induced in the heart after MI and that it can increase cardiac performance in rats with ischemic cardiomyopathy. Thus, in addition to catecholamine and angiotensin II, pro-TRH/TRH may be another important axis that affects hemodynamics and cardiac function in heart failure.

Key Words: hormones • heart failure • myocardial infarction • inotropic agents