Impact of hyperthyroidism on cardiac hypertrophy

Abstract

The cardiac growth process (hypertrophy) is a crucial phenomenon conserved across a wide array of species and is critically involved in the maintenance of cardiac homeostasis. This process enables an organism to adapt to changes in systemic demand and occurs due to a plethora of responses, depending on the type of signal or stimuli received. The growth of cardiac muscle cells in response to environmental conditions depends on the type, strength and duration of stimuli, and results in adaptive physiological responses or non-adaptive pathological responses. Thyroid hormones (TH) have a direct effect on the heart and induce a cardiac hypertrophy phenotype, which may evolve to heart failure. In this review, we summarize the literature on TH function in the heart by presenting results from experimental studies. We discuss the mechanistic aspects of TH associated with cardiac myocyte hypertrophy, increased cardiac myocyte contractility and electrical remodeling, as well as the associated signaling pathways. In addition to classical crosstalk with the sympathetic nervous system (SNS), emerging work pointing to the new endocrine interaction between TH and the renin-angiotensin system (RAS) is also explored. Given the inflammatory potential of the angiotensin II peptide, this new interaction may open the door for new therapeutic approaches which target the key mechanisms responsible for TH-induced cardiac hypertrophy.

Keywords: cardiac myocyte; cardiac remodeling; molecular mechanisms; renin-angiotensin system; thyroid hormones.

Figure 1

Some examples of thyroid hormones action on cardiomyocytes, which are upregulated in hyperthyroidism. Thyroid hormones (TH) might interact with cell surface receptors, such as integrin aVb3, to trigger the fast activation of cytoplasmic kinases, or it may enter the cell with the help of transporters such as MCT8. In the cytosol, much of T4 (tyroxine) is converted to T3 (triiodothyronine) by the action of the enzyme D2 (type 2 deiodinase). T3 then interacts with mitochondrial or cytoplasmatic receptors, affecting the activity of ion channels and the production of reactive oxygen species (ROS). This hormone also migrates to the nucleus and binds to thyroid hormone receptors (TR), forming a complex with high affinity for DNA-coupled thyroid response elements (TRE), although the T3-TR complex may interact with other DNA-bound proteins without the need to directly bind to chromatin to play its role. Thus, the transcription of several target genes is modulated, followed by protein synthesis, which ultimately results in cell hypertrophy.

Figure 2

Involvement of the RAS in cardiac hypertrophy induced by TH. AT1R activation triggers TH-mediated cardiac hypertrophy by activating the miR-208a/α-MHC, Akt/GSK3β/mTOR and NFkB pathways, and by downregulating miR-133. Additionally, AT2R contributes to cardiac growth in hyperthyroid rats by participating in Akt and TGF-β activation.Increased levels of Ang-(1–7) prevents the development of T3-induced cardiac hypertrophy by blocking GSK3β/NFATc3 activation via the MAS receptor. AGT, angiotensinogen; Ang I, angiotensin I; Ang II, angiotensin II; Ang-(1–9), angiotensin-(1–9); Ang-(1–7), angiotensin-(1–7); ACE, angiotensin I converting enzyme; ACE2, angiotensin II converting enzyme; AT1R, angiotensin II receptor type 1; AT2R, angiotensin II receptor type 2.