Time-sequence activation and relationship with cardiac functon of angiotensinogen, endothelin-1 and insulin-like growth factor-I gene expression in acutely overloaded pigs

The aim of the present study was to identify the relationship between angiotensinogen (AGT), endothelin-1 (ppET-1) and insulin-like growth factor-I (IGF-I) gene expression, and contractility of the left ventricle during the very early phase of pressure and volume overload in adult pigs. Eighteen adult farm pigs underwent aortic banding (60 mmHg aortic gradient), 18 underwent the creation of aorta-cava fistula (+65% cardiac output), and 12 were sham-operated. Hemodynamic and echocardiographic parameters, cardiac growth factor gene expression (expressed as GF/GAPDH ratio) and peptide release in coronary circulation were measured at baseline and 3, 6, 12, 24, 48 and 72 hours after surgical procedure. Transtenotic pressure gradient acutely increased after aortic banding (60 mmHg) and remained stable at following experimental times. End-systolic stress sharply increased and myocardial contractility (K stiffness) acutely decreased at 3 and 6h after banding, both returning at baseline at 12h, following the increased expression of AGT (16 times at 3h) and ppET-1 (112 times at 6h) genes. At 24h, after normalization of end-systolic stress and myocardial contractility, AGT and ppET-1 gene expression recovered and IGF-I gene expression significantly rose (37 times). At 72h, in the presence of enhanced IGF-I gene expression, left ventricular mass was significantly increased (+23%, p<0.05). In situ hybridization studies demonstrated mRNA expression for all factors in cardiomyocytes. Changes in specific mRNA expression were followed by release of active GF peptides in coronary circulation. In volume overloaded animals contractility was not decreased, the AGT gene was mildly upregulated at 6h and ppET-1 gene expression remained unchanged. IGF-I gene expression was upregulated at 24h preceding the onset of myocardial hypertrophy. In conclusion: 1) a different pattern of GF activation is involved in acute cardiac adaptation response to pressure versus volume overload, 2) growth factors initially support myocardial contractility and thereafter induce myocardial hypertrophy.