Antisense to Epidermal Growth Factor Receptor Prevents the Development of Left Ventricular Hypertrophy

Abstract

Abstract-We previously demonstrated that left ventricular hypertrophy (LVH) induced by angiotensin II infusion requires epidermal growth factor receptor (EGFR) activation to mediate the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway. To test whether the EGFR-mediated MAPK/ERK activation plays an important role in development and maintenance of LVH in spontaneously hypertensive rats (SHR), we investigated the effects of antisense oligodeoxynucleotide to EGFR (EGFR-AS) on LVH and blood pressure in young and adult SHR. EGFR-AS, sense oligonucleotide to EGFR (EGFR-S; 1.5 mg/kg), or vehicle control (5% dextrose) with liposome was injected once a week for 2 months in 5-or 13-week-old SHR. The effect of EGFR-AS on the expression of EGFR and phosphorylated ERK in the heart were examined by Western blots. After treatment, EGFR-AS significantly (PϽ0.05) decreased left ventricular weight/body weight and blood pressure in young SHR compared with EGFR-S or control-treated rats. In adult SHR, EGFR-AS did not affect left ventricular weight/body weight and blood pressure. EGFR and phosphorylated ERK significantly declined from 5 to 20 weeks (PϽ0.05). EGFR-AS, but not EGFR-S, significantly (PϽ0.05) decreased the expression of EGFR and phosphorylated ERK in young SHR, but had no significant effect in adult SHR. These results suggests that EGFR-mediated ERK activation is critically important for LVH in young SHR. n patients with essential hypertension in which plasma renin activity is normal, ACE inhibitors or angiotensin (Ang) II type 1 receptor (AT1R) antagonists lower blood pressure (BP) and regress left ventricular hypertrophy (LVH). 1,2 This indicates the importance of the local renin angiotensin system in cardiovascular regulation and remodeling. Ang II promotes cell growth in vitro and induces LVH in rats without the elevation of BP. 3 The induction of cell growth by Ang II requires the activation of mitogen-activated protein kinase (MAPK) pathway through tyrosine kinase activation. 4 However, AT1R itself does not have a tyrosine kinase domain. We previously reported that the epidermal growth factor receptor (EGFR), which is a receptor-type tyrosine kinase, plays an important role in LVH in Ang II-infused hypertensive rats through the activation of extracellular signal-regulated kinase (ERK), one of the MAPK family members. 5 A greater reactivity of blood vessels 6 and enhanced mitogenic responses of aortic myocytes 4,7 to Ang II have been reported in spontaneously hypertensive rats (SHR). Ang II infusion increases EGFR mRNA 8 and protein in the aorta and heart. 5 EGFR protein levels are elevated in the kidney and aorta from genetically hypertensive rats. 9 The activities of ERKs in the heart were elevated in young SHR and decreased with age. 10,11 However, there is no direct evidence regarding the contribution of EGFR to ERK activation in the development and maintenance phase of hypertension and LVH in SHR. To address this question, we developed an effective antisense oligonucleot...

EF Domains Are Sufficient for Nongenomic Mineralocorticoid Receptor Actions

“…Therefore, these truncated variants represent a tool to differentiate the consequences of nongenomic and genomic signaling and may help us to learn more about the pathophysiological relevance of nongenomic signaling. It has been shown that the EGFR-ERK1/2 signaling pathway plays a central role in cardiovascular fibrosis (53,54). Thus, the activation of this pathway by nongenomic MR signaling could contribute to its pathophysiological effects on cardiovascular tissue (4).…”

Epidermal Growth Factor Receptor Inhibitor PKI-166 Governs Cardiovascular Protection without Beneficial Effects on the Kidney in Hypertensive 5/6 Nephrectomized Rats

“…Further, EGF acts as a potent vasoconstrictor of arteries (Florian and Watts, 1999), and increased EGFR expression was found in the hypertrophied left ventricle (LV) of spontaneous hypertensive rats (Fujino et al, 1998). Also, receptor tyrosine kinase inhibitors, such as EGFR tyrosine kinase inhibitor 4-(39-chloroanilino)-6,7-dimethoxyquinazoline (AG1478), and EGFR antisense oligonucleotides attenuate vasoconstriction and elevation of blood pressure in Ang II-induced hypertension (Kagiyama et al, 2002(Kagiyama et al, , 2003.…”

Consequences of Epidermal Growth Factor Receptor (ErbB1) Loss for Vascular Smooth Muscle Cells From Mice With Targeted Deletion of ErbB1

“…15,23,24 The importance of EGFR in mediating pathophysiological effects of heterologous signaling systems is supported by its role in endothelin-induced fibrogenic effects. 15 Endothelin-induced phosphorylation of the mitogen-activated protein kinase and endothelin-induced increase in collagen I gene activity were completely prevented by an inhibitor of the EGFR kinase.…”