Impairment of Myocyte Contractility Following Coronary Artery Narrowing Is Associated with Activation of the Myocyte IGF1 Autocrine System, Enhanced Expression of Late Growth Related Genes, DNA Synthesis, and Myocyte Nuclear Mitotic Division in Rats

To determine whether the alterations in ventricular loading and myocyte cellular contractile performance produced by short-term coronary artery constriction were associated with the activation of genes implicated in myocyte DNA synthesis including changes in the expression of insulin-like growth factor-1 (IGF₁) and insulin-like growth factor-1 receptors (IGF₁-R), nonocclusive coronary artery narrowing (CAN) was induced in rats. Animals were examined 2 and 7 days after coronary constriction. Following the in vivo documentation of severe impairment of ventricular performance, estimations of single-cell mechanics in vitro showed that peak shortening was decreased in left and right myocytes of coronary stenosed rats. Moreover, time to peak shortening was prolonged whereas velocity of shortening was decreased. These defects in myocyte contractility were accompanied by increases in cell length and width, indicative of myocyte enlargement biventricularly. In addition, CAN led to an enhanced expression of proliferating cell nuclear antigen (PCNA) and histone-H₃ genes in myocytes at 2 and 7 days after surgery. PCNA protein was also detected in these stressed cells. These molecular responses were associated with increases in mRNA for IGF₁ and IGF₁-R in combination with enhanced DNA synthesis and appearance of myocyte nuclear mitotic division. In conclusion, cardiac myocytes may respond to the elevation in wall and myocyte stress by activating an IGF₁-IGF₁-R autocrine system which may modulate the induction of late growth related genes which are essential for DNA replication and myocyte cellular hyperplasia.