Melatonin ameliorates β‐aminopropionitrile fumarate‐induced acute aortic dissection in rats by reducing vascular inflammatory response and smooth muscle proliferation and migration

Acute aortic dissection (AAD), characterized by abrupt and often extensive tears in the inner layer of the aortic walls, is a complex and critical vascular disease. Like most degenerative diseases, risk factors of typical cardiovascular diseases were all associated with AAD. Recent evidence supports that vascular inflammation and oxidative stress play a crucial role in the progression of AAD. Using β‐aminopropionitrile fumarate (BAPN), a potent lysyl oxidase inhibitor, we developed a consistent rat model for AAD that exhibits certain characteristics found in human tissues. Melatonin is a potent antioxidant and a scavenger of hydroxyl radicals, and has been demonstrated to possess anti‐inflammatory and anti‐angiogenic effects on tissues. Our study objective is to investigate the effects of melatonin on progression of BAPN‐induced AAD. Methods 54 male 4‐week‐old Sprague‐Dawley rats, weighted between 75–100 g, were divided evenly into a sham, an AAD and a melatonin‐treated AAD group (MEL). AAD can be induced by BAPN (2g/L) administered in the drinking water for ~4 weeks. Melatonin (20 mg/kg; bolus) was treated intraperitoneally twice daily to the MEL group; concurrently, equal amount of saline was treated (bolus, i.p.) to the sham and AAD group. The body weight and amount of food and drink consumption of each rat were measured daily and the intake of BAPN was calculated. Blood pressure (BP) was measured every other day, using a tail‐cuff system. 6 rats from each group were sacrificed at the 14 th , 21 st and 28 th day for aortic histology, wall thickness at arch (TH), and protein and mRNA expressions of aorta. Results Daily intake of BAPN in AAD and MEL group was calculated as 0.413±0.014 and 0.410±0.014 mg/kg/day, respectively. At the end of 4 weeks of breeding, intramural hematoma and degrading smooth muscle cells were exhibited in all remaining 6 rats in the AAD group, but one in the MEL group. Typical aortic morphology (upper) and sectioned tissue (lower) stained by hematoxylin and eosin stain were shown in Fig. 1. BAPN treatment increased BP and pulse pressure in both AAD (94.1±3.7; 72.0±3.6 mmHg) and MEL (90.8±5.8; 66.3±5.2 mmHg), compared to the sham group (88.1±1.6; 42.4±1.9 mmHg). TH measured in MEL (excluding the damaged) and sham were relatively invariant during the time course of 4 weeks (68.1±4.6; 66.1±2.5 mm). In contrast, TH measured in AAD started to increase at the 21 st (77.2±5.5 mm) and 28 th day (91.4±6.4 mm). Protein expressions of fibrillin‐1 and nuclear factor‐κB expression in AAD were markedly increased relative to sham (118±2; 271±14%), and notably reduced in MEL (110±2; 152±7%). Also, mRNA expressions in AAD were all increased, and notably reduced in MEL relative to sham, including those associated with inflammation, e.g. transforming growth factor‐β (330±92; 102±25%), cyclooxygenase‐2 (152±52; 88±30%), inducible nitric oxide synthase (147±63; 74±18%), and vascular smooth muscle (VSM) migration and proliferation, e.g. phosphodiesterase4D2 (146±45; 46±4%), Ca 2+ /calmodulin‐dependent protein kinase 2δ (244±85; 105±42%) and placental growth factor (320±120; 42±6%). Conclusions Melatonin protects aorta against BAPN‐induced AAD by reducing vascular inflammatory responses, and attenuates VSM migration and proliferation. Support or Funding Information Ministry of Science and Technology 104‐2320‐B‐030 ‐004 to Dr. JIUN‐JR WANG and Chi‐Mei Foundation Hospital (Tainan) 104‐CM‐FJU‐07 to Drs. JIUN‐JR WANG and NAN‐CHUN WU