Nicholas F. Paoni

Beneficial effects of growth hormone and insulin-like growth factor-1 in experimental heart failure in rats treated with chronic ACE inhibition

Summary: The effects of growth hormone (GH) plus insulin-like growth factor-1 (IGF-1) were tested in an experimental model of cardiac failure treated with chronic angiotensin-converting enzyme (ACE) inhibition. Myocardial infarction was induced in rats by left coronary artery ligation. Two weeks after ligation, the animals received either captopril (2 g/L in drinking water) or water for 3 months. The rats were then given either GH (2 mg/ kg/day) plus IGF-1 (2 mg/kg/day) or vehicle for 14 days. Captopril treatment decreased mean arterial pressure (MAP), left ventricular end-diastolic pressure (LVEDP) and systemic vascular resistance (SVR) (p < 0.05), and increased cardiac index (CI) and stroke volume index (SVI) (p < 0.05). GH/IGF-1 or captopril + GH/IGF-1 treatment decreased MAP, LVEDP, and SVR (p < 0.05), and increased left ventricular maximum dP/dt, CI, and SVI (p < 0.05). The increases in CI and SVI were significantly greater in the captopril + GH/IGF-1-treated animals than in those treated with captopril alone (p < 0.05). The beneficial effect of captopril in reducing cardiac hypertrophy was preserved in the captopril + GH/IGF-1 group. The results indicate that GH/IGF-l and captopril can improve cardiac performance in congestive heart failure by independent and complementary mechanisms.

Stanniocalcin 1 Is an Autocrine Modulator of Endothelial Angiogenic Responses to Hepatocyte Growth Factor

Stanniocalcin 1 (STC1) is a secreted glycoprotein originally described as a hormone involved in calcium and phosphate homeostasis in bony fishes. We recently identified the mammalian homolog of this molecule to be highly up-regulated in an in vitro model of angiogenesis, as well as focally and intensely expressed at sites of pathological angiogenesis (e.g. tumor vasculature). In the present study, we report that STC1 is a selective modulator of hepatocyte growth factor (HGF)-induced endothelial migration and morphogenesis, but not proliferation. STC1 did not inhibit proliferative or migratory responses to vascular endothelial growth factor or basic fibroblast growth factor. The mechanism of STC1 inhibitory effects on HGF-induced endothelial migration seem to occur secondary to receptor activation because STC1 did not inhibit HGF-induced c-met receptor phosphorylation, but did block HGF-induced focal adhesion kinase activation. In the mouse femoral artery ligation model of angiogenesis, STC1 expression closely paralleled that of the endothelial marker CD31, and the peak level of STC1 expression occurred after an increase in HGF expression. We propose that STC1 may play a selective modulatory role in angiogenesis, possibly serving as a “stop signal” or stabilizing factor contributing to the maturation of newly formed blood vessels. HGF is a mesenchyme-derived pleiotropic factor with mitogenic, motogenic, and morphogenic activities on a number of different cell types. HGF effects are mediated through a specific tyrosine kinase, c-met, and aberrant HGF and c-met expression are frequently observed in a variety of tumors. Recent studies have shown HGF to be a potent growth factor implicated in wound healing, tissue regeneration, and angiogenesis.

Effects of early treatment with growth hormone on infarct size, survival, and cardiac gene expression after acute myocardial infarction

OBJECTIVE This study examined the effects of growth hormone (GH) on infarct size, survival, and cardiac gene expression in rats with acute myocardial infarction. DESIGN Animals randomly received sc injection of either saline vehicle (n = 98) or GH (2mg/kg/day, n = 105) for 14 days commencing the day of left coronary artery ligation. Infarct size was determined by morphometric analysis at the time of death or at 52 weeks post-surgery. Gene expression was analyzed by real-time RT-PCR after 2-week treatment. RESULTS GH decreased infarct size by 18% (P < 0.01) and increased survival by 36% at 52 weeks. GH also significantly reduced cardiac expression of atrial natriuretic factor, beta-myosin heavy chain, alpha-smooth muscle actin, collagen I, collagen III, fibronectin, and pro-inflammatory cytokines. CONCLUSIONS Treatment with GH for 2 weeks beginning on the day of myocardial infarction produced beneficial effects that were associated with reductions in cardiac gene expression symptomatic of pathological remodeling.

Expression profiling techniques for cardiac molecular phenotyping.

Evidence from clinical and experimental heart failure studies indicates that cardiac growth and morphogenesis are important determinants for morbidity and mortality. Characterization of the myocardial gene expression patterns that are associated with these processes may be useful in the search for novel therapeutic strategies. Changes in tissue mRNA abundance have traditionally been monitored by a candidate gene approach, in which transcripts of interest have been analyzed one or several at a time. New methodologies for detecting differentially expressed genes, such as DNA microarrays, and restriction fragment display, are now enabling molecular phenotyping to be performed on a much larger scale. Here we describe our work on the application of these methods and the insights gained into the biology and pathophysiology of the myocardium.