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Cardiovascular Research 1999 43(2):282-284; doi:10.1016/S0008-6363(99)00165-0
© 1999 by European Society of Cardiology
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Copyright © 1999, European Society of Cardiology

Sarcoplasmic reticulum Ca2+ ATPase gene expression to the rescue of myocardial contractility in hypothyroid associated heart failure

Carlo Venturaa,b,*, Gianfranco Pintusa,b and Margherita Maiolia,b

aDepartment of Biomedical Sciences, Division of Biochemistry, Laboratory of Cardiovascular Research, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy
bNational Laboratory of the National Institute of Biostructures and Biosystems, 07033 Osilo, Italy

* Corresponding author

Received 22 April 1999; accepted 22 April 1999

See article by Bluhm et al. [18] (pages 382–388) in this issue.

Recent advances in animal genetics and transgenic technology have blossomed into one of the dominant strategies to explore the consequences of gene defects in different organ systems in the in vivo context. Such a perspective has been progressively applied to the cardiovascular system to dissect complex in vivo physiologic and pathologic states. The encouraging results achieved so far in the field of heart hypertrophy and failure with the aid of engineered mouse models have even suggested consideration for the cardiovascular system as a paradigm for other complex apparata, including the pulmonary, renal and neural systems [1].

It is now becoming increasingly evident that the myocardial cell, besides being a target for a number of hormones and growth factors [2,3] also behaves as a source for peptides that may play a crucial role in signal transduction processes in the heart [4–7]. Hence, the myocardium adapts to hormonal, genetic and mechanical stimuli by triggering a number of paracrine, autocrine and intracrine responses that represent the plight that is impacting the homeostasis of the myocardial cells throughout specific pathologic processes [8–11]. The complexity of the overall picture is given by the finding that heart mechanical dysfunctions and failure are often the functional end-point of processes involving an impairment of the architectural plan of the myocardial cell [1,12]. In this regard, heart development is one of the first morphogenetic events occurring in the embryo and is a complex phenomenon involving cell proliferation and differentiation, as well as tissue organization. The observation that a recapitulation of the fetal program occurs during myocardial hypertrophy has led to the proposal that hypertrophy itself may recapitulate ontogeny [13–15]. Therefore, the heart failure process that occurs in the context of myocardial hypertrophy or complex metabolic disorders that impact the cardiovascular system is closely entangled with the impairment of the myocyte program of growth and differentiation. These considerations pose the problem of identifying endogenous molecules that can restore the myocardial contractility in the course of diseases bearing a complex genetic background, including different types of acquired or genetically determined myocardial hypertrophy, hereditary cardiomyopathies, and cardiomyopathic processes associated with diabetes or hypothyroidism. The calcium pump, or Ca2+-ATPase of the sarcoplasmic reticulum (SERCA2a) is now recognized as a major regulator of cardiac contractile function. This pump drives the Ca2+ uptake into the sarcoplasmic reticulum, therefore accounting for the speed of cardiac relaxation. Consonant with a crucial role of SERCA2a in contractile regulation is the observation that a decrease in SERCA2a gene expression and activity can be observed in a wide variety of pathological conditions associated with cardiac hypertrophy and/or failure [16,17].

In this issue of Cardiovascular Research, Bluhm et al. [18] examined the possibility that transgenic gene expression of SERCA2a in mice may compensate for the abnormalities in cardiac performance associated with pharmacologically-induced hypothyroidism. The authors assessed SERCA2a gene and protein expression in hearts from euthyroid and hypothyroid mice of wild-type or SERCA2a transgene status. The study revealed a decrease in SERCA2a mRNA and protein expression in hypothyroid wild-type animals, as compared with euthyroid wild-type mice. Such a decrease was associated with a prolongation in the time course of both the contraction and relaxation in isolated papillary muscles. When transgenic mice overexpressing SERCA2a were made hypothyroid, the expression of SERCA2a mRNA did not differ from that observed in euthyroid wild-type mice. Noteworthy, the increase in SERCA2a mRNA and protein detected in hypothyroid transgene mice in comparison to hypothyroid wild-type animals was able to elicit a functional improvement in both the contraction and relaxation profile of papillary muscle. Such a restoration of the contractile performance appears to be specifically linked to the overexpression of the SERCA2a gene elicited in transgenic mice, since a previous characterization of the SERCA2a transgenic model performed by the same group [19] revealed no changes in the expression of other calcium handling-related genes, including the genes encoding for the ryanodine receptor, calsequestrin, phospholamban and the Na+/Ca2+-exchanger.

Demonstration of the feasibility of a transgene-mediated functional approach in the rescue of a hypothyroid phenotype may both disclose new perspectives and place new challenges. In the study by Bluhm et al. [18], mice were made hypothyroid at the age of 2 to 3 months, a period in the adult life span which is far away from the developmental changes occurring in the embryo during the specification of the cardiac lineage. It is now documented that thyroid hormones may deeply affect myocardial growth and differentiation [20,21]. These hormones act on nuclear receptors belonging to the Steroid–Thyroid–Retinoid superfamily of transcription factors. This superfamily of transcription factors is structurally related to the class of zinc finger proteins that display domains with defined functions for binding to ligands, DNA and other receptors in order to form combinatorial transactivation motifs. In particular, 3,5,3'-Triiodo-L-Thyronine (T3) has been shown to activate the retinoic X receptor-{alpha} (RXR{alpha}) and to regulate its level of expression in the heart [22]. Moreover, compelling evidence has been recently provided indicating that RXR{alpha} acts as a morphogen in the normal cardiac development. In this regard, RXR{alpha}–/–mouse embryos have been found to display an embryonic form of congestive heart failure that initially manifests itself as a decrease in ventricular contractile function and displays important features of ventricular dysmorphogenesis, including ventricular chamber hypoplasia as well as disorders of ventricular trabeculation and septation [23]. Therefore, hypothyroidism arising during the early embryonic development is likely associated to a decrease in the level of RXR{alpha} that appears to be reflected by the aberrant temporal and spatial pattern of expression of a panel of critical cardiac genes that are important regulators of cellular commitment to the cardiac lineage. Among these genes, the NK-2 class homeobox gene product Nkx-2.5/Csx and the retinoic acid-inducible GATA-4 transcription factor, a member of the zinc finger-containing GATA factors, have been shown to play a crucial role in triggering myocardial differentiation and in specifying the architectural plan of the cardiac myocyte [24,25].

Future directions in the dissection of the interplay(s) among the molecular determinants that define a normal myocardial architecture and contractility will involve the development of engineered mouse models overexpressing these cardiac morphogenetic elements. These animal models will represent a valuable tool for investigating whether genes targeted for mammalian cardiogenesis and potentially involved in the restoration of a normal cardiac morphogenesis may also act to rescue a normal contractile activity. The establishment of these engineered animals will also help to understand whether ventricular chamber dysfunctions simply arise as a result of decreased number and/or altered architecture of cardiac myocytes or whether a primary contractile defect is associated with an impaired program of cardiogenesis. Addressing this issue may be of particular relevance in the course of metabolic disorders, including hypothyroidism and diabetes, that encompass both a derangement of cardiac architecture and an impairment of myocardial contractility.


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