Abstract 455: Role of Transcription Co-Factor Friend of GATA 2 (FOG2) in a Hypertensive-Diabetic Mouse Model of Coronary Microvascular Disease

Abstract

Coronary microvascular disease (CMVD) - disease of the coronary pre-arterioles, arterioles, and capillaries – has become an increasingly well-recognized cardiac pathology. Characterized by microvascular remodeling, wall thickening, lumen obliteration, endothelial dysfunction, capillary rarefaction, and perivascular immune cell infiltration, it can lead to inadequate myocardial perfusion, angina, heart failure, or myocardial infarction. Despite these clinical ramifications, our understanding of the pathophysiology of CMVD remains nascent. Friend of GATA 2 (FOG2, also called ZFPM2) is a transcriptional co-factor which is crucial in coronary development; and cardiomyocyte expression of FOG2 is required for the maintenance of the coronary microvasculature in adult mice. We hypothesize that FOG2 is activated in CMVD, and that Hypoxia-Inducible Factor 1a (HIF1a) may play a role in FOG2 activation. To test this hypothesis, we developed a hypertensive-diabetic (HTN/DM) mouse model of CMVD. Briefly, adult female C57BL/6 mice were treated with Angiotensin II (1mg/kg/day SQ osmotic pump for 8 weeks) and low-dose streptozotocin (35 mg/kg IP for 4 days) (n=5) or saline (n=4). HTN/DM mice had increased systolic blood pressure (141.7±1.6 vs 109.2±1.1 mmHg, p<0.0001), mild fasting hyperglycemia (181.8±8.5 vs 148.8±9.8 mg/dl, p=0.04), and decreased glucose tolerance (p<0.0003). HTN/DM mice had evidence of mild LV hypertrophy, preserved EF, and diminished coronary hyperemic velocities by echocardiography. Histology revealed microvascular pathology (vessel wall thickening and immune cell infiltration) and decreased cardiac capillary density (148.8±9.8 vs 163.8±4.3 phf, p=0.008). FOG2 protein was increased in HTN/DM mouse hearts (p<0.05). Treatment of AC16 cardiomyocytes with HIF-activator hydroxylase inhibitor DMOG showed a dose-dependent increase in FOG2 expression and protein nuclear translocation. In summary, we modeled CMVD in mice using mild hypertensive-diabetic insults which are relevant to human disease. We found that FOG2 protein is increased in CMVD suggesting that FOG2 may be relevant to adult CMVD pathophysiology in vivo . We additionally provide in vitro evidence that FOG2 is induced in HIF-activating conditions .