Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction

Abstract

Thyroid hormone (TH) is critical for cardiac development and heart function. In heart disease, TH metabolism is abnormal, and many biochemical and functional alterations mirror hypothyroidism. Although TH therapy has been advocated for treating heart disease, a clear benefit of TH has yet to be established, possibly because of peripheral actions of TH. To assess the potential efficacy of TH in treating heart disease, type 2 deiodinase (D2), which converts the prohormone thyroxine to active triiodothyronine (T3), was expressed transiently in mouse hearts by using the tetracycline transactivator system. Increased cardiac D2 activity led to elevated cardiac T3 levels and to enhanced myocardial contractility, accompanied by increased Ca 2؉ transients and sarcoplasmic reticulum (SR) Ca 2؉ uptake. These phenotypic changes were associated with up-regulation of sarco(endo)plasmic reticulum calcium ATPase (SERCA) 2a expression as well as decreased Na ؉ ͞Ca 2؉ exchanger, ␤-myosin heavy chain, and sarcolipin (SLN) expression. In pressure overload, targeted increases in D2 activity could not block hypertrophy but could completely prevent impaired contractility and SR Ca 2؉ cycling as well as altered expression patterns of SERCA2a, SLN, and other markers of pathological hypertrophy. Our results establish that elevated D2 activity in the heart increases T3 levels and enhances cardiac contractile function while preventing deterioration of cardiac function and altered gene expression after pressure overload.calcium ͉ cardiac hypertrophy ͉ sarcoplasmic reticulum ͉ deiodinase ͉ transgenic mice T hyroid hormone (TH) is essential for normal development in vertebrates (1), with TH levels rising postnatally and peaking in the third week of life (2). This surge is critical for fetal-to-adult switch in the cardiac gene program and is responsible for changes in Ca 2ϩ homeostasis, myosin isozyme content [␣-myosin heavy chain (MHC)-to-␤-MHC switch], and action potential profile (3, 4). Intriguingly, the genetic and functional changes associated with heart failure, such as reduced Ca 2ϩ transients and ␣-MHC-to-␤-MHC shifts, which recapitulate the fetal gene program, are also observed in hypothyroidism (5, 6). In addition, TH metabolism and signaling are abnormal in heart failure (5, 7, 8). For example, circulating and cardiac triiodothyronine (T3) levels (i.e., active TH) are reduced in advanced heart disease, after acute myocardial infarction, and in patients with cardiopulmonary bypass. These T3 changes occur in association with decreased peripheral conversion of thyroxine (T4) into T3 (5, 8) and elevated cardiac deiodinase type 3 (D3) activity (9). TH receptor expression is also altered in pathological hypertrophy (10), and myocardial contractility is impaired in mice lacking TH receptors (11). Not surprisingly, TH and its analogue 3,5-diiodothyropropionic acid (DITPA) have been advocated for treating heart failure (12, 13) and for reversing cardiac dysfunction in patients with hypothyroidism (5), although TH use has been limited by car...

Time-dependent changes in the expression of thyroid hormone receptor α1 in the myocardium after acute myocardial infarction: possible implications in cardiac remodelling

“…THdegrading deiodinase activation was shown to be increased in rats with cardiac hypertrophy and failure, an effect which may contribute to local hypothyroid state (4). Furthermore, overexpression of the type 2 deiodinase in mouse heart (converting T 4 to active T 3 ), prevented pressure overload-induced cardiac dysfunction (5).…”

Ablation of sarcolipin enhances sarcoplasmic reticulum calcium transport and atrial contractility

“…SLN expression is regulated during cardiac and skeletal muscle development (2)(3)(4). Furthermore, SLN expression levels are altered in atria during cardiac pathology both in animal models (2,4,(11)(12)(13) and in humans (14), suggesting that SLN levels may play an important role in maintaining atrial Ca 2ϩ homeostasis during cardiac pathophysiology.…”

Differential expression of sarcolipin protein during muscle development and cardiac pathophysiology

“…SLN mRNA expression is shown to be developmentally regulated [4,5] and is altered by thyroid hormones [9,10] and pathophysiological conditions [3,4,[11][12][13]. Pressure-overloaded hypertrophy induced by transverse aortic constriction in mice or by monocrotaline administration in rats significantly decreased the expression of SLN, SERCA2a, and phospholamban mRNAs in the atrium [13].…”