Role of the phosphoinositide signalling system in the genesis of cardiac hypertrophy.

The genesis of left ventricular hypertrophy in hypertension is usually regarded as a physiological response to increased haemodynamic load. However, there is growing evidence that the presence of cardiac hypertrophy is an independent and important risk factor for cardiovascular morbidity and mortality. Therefore, it is of fundamental importance to delineate the mechanisms by which cardiac growth occurs but at present these processes are ill understood. In certain cells control of growth is thought to involve the hydrolysis of inositol lipids and the induction of protooncogenes. Moreover, several of the stimuli which may initiate cardiomyocyte growth, such as myocardial wall stretch, a1 and angiotensin II receptor agonists, also stimulate cardiac phosphoinositide turnover. This thesis considers the hypothesis that phosphoinositide metabolism is increased in the left ventricle during the development of cardiac hypertrophy. Three related proto-oncogenes were also studied: rasH, which may encode the G protein (Gp) and the nuclear proto-oncogenes c-myc and c-fos which are induced following activation of this pathway. Two models of hypertension were studied; a genetic form called the spontaneously hypertensive rat (SHR) and coarctation hypertension using a ligature placed on the abdominal aorta. Significant hypertension was induced following coarctation of the aorta compared with sham operated animals both at 3 and 9 days. There was cardiac hypertrophy demonstrable at 3 and 9 days which progressed further by 28 days. Following a 2 hour incubation with [3H] inositol, labelled Ins1,4,5P3 and InsP2 were increased in the left ventricle of the coarctation group at 3 days. By 9 days these differences were no longer sustained. Moreover, total Ins1,4,5P3 was increased at 3 days in the hypertensive group compared with sham operated animals but were not significantly different at 9 days. At 3 days levels of rasH, c-myc and c-fos had increased in animals with coarctation. However, by 9 days the levels of rasH and c-myc decreased in the hypertensive group compared with control animals. No difference was observed in c-fos between the two groups. Spontaneously hypertensive rats were hypertensive by 5 weeks of age compared to the normotensive control group (Wistar Kyoto, WKY) and the blood pressure increased further by 12 weeks. Cardiac hypertrophy was observed at 5 and 12 weeks. Accumulation of [3H] inositol monophosphate within the left ventricle in the presence of lithium was not different at either 5 or 12 weeks of age. There was no significant difference in labelling of Ins1,4,5P3 at 5 weeks or total Ins1,4,5P3 at 5 and 12 weeks of age. There was a significantly lower level of rasH at both 5 weeks and at 12 weeks of age in the SHR compared with WKY. No differences were observed in c- myc or c-fos levels in either strain at these ages. It is concluded that myocardial phosphoinositide metabolism and levels of certain related proto-oncogenes were increased during the early stages of the development of cardiac hypertrophy in coarctation hypertension. Such processes may be involved in the initial phase of the genesis of cardiac hypertrophy in this model