Recently we have shown that interactions between overly stressed cardiomyocytes in hypertensive hearts and CD8+ T cells results in the development of cardiac fibrosis using mouse models (manuscript in preparation).
We will extend these studies by focusing on inhibiting NKG2D/MICA interactions to prevent the development of cardiac fibrosis associated with primary hypertension using spontaneously hypertensive rats; this model much more closely resembles essential hypertension in humans than any mouse model. MICA is expressed by stressed cardiomyocytes and NKG2D receptors are expressed on memory CD8+ T cells present in a hypertensive heart. Using the knowledge that MICA amino acid sequences within its α1 and α2 domains interact with NKG2D, we will develop a vaccination strategy that generates anti-MICA antibodies to prevent MICA binding with NKG2D for therapy. This strategy has been recently used to generate experimental vaccines that prevent PCSK9-LDLR interactions. We will monitor anti-MICA antibody levels, levels of autoreactive T cells and affects downstream of MICA/NKG2D interactions including left ventricular fibrosis, cardiomyocyte apoptosis, cardiac TGF-beta1 and receptor-expressing cells, cardiac macrophages and left ventricular diastolic function by echocardiography; NKG2D+CD8+ T cells, blood pressure and left ventricular hypertrophy will also be assessed. We expect that inhibiting NKG2D/MICA interactions will also prevent the slow-developing cardiac fibrosis associated with primary hypertension.