Search

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.

The microvascular endothelium in endocrine glands is very permeable to circulating substances and secretory products, reflecting the need for rapid hormone release in response to homeostatic stimuli. Fenestrae, specialized discontinuities of the endothelial plasma membrane, presumably permit high permeability, but their presence does not strictly correlate with the expression of vascular endothelial growth factor (VEGF). The authors have identified a distinct angiogenic mitogen selective for endocrine-gland endothelium. It is very similar biologically to VEGF and is able to induce fenestration in target cells, but it does not exhibit structural homology with the family of VEGF proteins. Expression of this factor, termed endocrine gland-derived VEGF (EG-VEGF), is largely restricted to steroidogenic glands. When a library of purified human secreted proteins was screened for their ability to promote the proliferation of bovine adrenal cortex-derived endothelial (ACE) cells (which respond to VEGF), EG-VEGF was identified as the only one that could induce a reproducibly strong mitogenic response. The increase in ACE cells exposed to EG-VEGF was very similar to that induced by VEGF, and both of these substances induced fenestration of endothelial cells. The expression of EG-VEGF was induced by hypoxia, which strongly promotes angiogenesis under both physiological and pathological conditions. On testing a wide range of human tissues and cell lines, EG-VEGF was found only in ovary, testis, adrenal, placenta, and (to a lesser degree) prostate. Using adenovirus to deliver EG-VEGF locally in a sustained manner, frank angiogenesis was observed with mitotic endothelial cells, edema, and granulation tissue. EG-VEGF protein was produced at a high level in skeletal muscle. Intraovarian delivery of either EG-VEGF or VEGF adenovirus led to marked enlargement of the ovaries, grossly visible blood vessels, and areas of hemorrhage. Microscopy revealed intense angiogenesis at the periphery of ovarian cysts. Steroidogenic glands may have developed highly specific local mechanisms that serve to "fine tune" the action of the VEGF receptors. EG-VEGF is one of a class of highly specific mitogens that help regulate the proliferation and differentiation of vascular endothelium in a tissue-specific manner. Mitogens specific for cardiac or skeletal muscle endothelium might hold great therapeutic potential.