Abstract
The use of histone deacetylase (HDAC) inhibitor is a novel therapeutic strategy for cardiovascular disease. Studies have shown that many HDAC inhibitors have the ability to reduce the aortic remodeling in various animal models. We hypothesized that the HDAC inhibitor, MGCD0103 (MGCD), attenuates aortic remodeling in rats under pressure overload-induced by transverse aortic constriction (TAC). The aortic ring tension analysis was conducted using the thoracic aorta. Sections of the aorta were visualized after hematoxylin and eosin, trichrome, and Verhoeff-van Gieson staining, and immunohistochemistry. The expression of genes related to aortic remodeling (αSMA, Mmp2, and Mmp9) and angiotensin receptors (Agtr1 and Agtr2) was determined by quantitative real-time polymerase chain reaction. There was a significant decrease in relaxation of the aorta when treated with MGCD. Fibrosis of the aortic wall and expression of angiotensin receptors increased in TAC rats, which was attenuated by MGCD. These results indicate that MGCD, an HDAC inhibitor, attenuates aortic remodeling in rats with TAC-induced pressure overload rats and may serve as a potential therapeutic target of antiaortic remodeling in pressure overload-induced hypertension-related diseases.
Highlights
Thoracic aortic diseases such as thoracic aortic aneurysms and aortic dissections are rarely diagnosed until symptoms appear, at which point patients risk a fatal aortic rupture [1]
transverse aortic constriction (TAC) resulted in a systolic blood pressure increase of approximately 40 mmHg, which was attenuated to approximately 30 mmHg by the administration of MGCD (Figure 1(a))
We investigated the expression level of αSMA mRNA by qRT-PCR. mRNA expression of αSMA (Figure 4(d)) was significantly (∗p < 0:05) higher in the TAC rats, consistent with the hypertrophy observed during histological evaluation. mRNA expression of αSMA decreased with MGCD treatment in TAC plus MGCD rats
Summary
Thoracic aortic diseases such as thoracic aortic aneurysms and aortic dissections are rarely diagnosed until symptoms appear, at which point patients risk a fatal aortic rupture [1]. Hypertension is well known as the most common risk factor for thoracic aortic diseases, but it is still not fully understood how increased pressure on the ascending aorta leads to aortic remodeling [2]. The current clinically used antihypertensive medications are diuretics, which flush the body of excess sodium and water; beta-blockers, which reduce heart rate and workload; angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, which regulate the renin-angiotensin system; and calcium channel blockers, which relax smooth muscle cells. Beta-blockers have traditionally been the treatment of choice for thoracic aortic diseases as they alter blood pressure. The angiotensin II receptor blocker losartan helps reduce the rate of aortic aneurysm expansion [4, 5]. Since angiotensin II can trigger aortic aneurysm in mice, angiotensin II signaling has a role in aortic aneurysm formation, and several aortic remodeling animal models have demonstrated the importance of angiotensin II receptors in angiotensin II signaling [6,7,8]
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