Tratsiakovich Yahor, Kiss Attila, Gonon Adrian T, Yang Jiangning, Sjöquist Per-Ove, Pernow John
1 Unit of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
2 Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden.
Diab Vasc Dis Res. 2017 May;14(3):236-245. doi: 10.1177/1479164116687935. Epub 2017 Feb 9.
RhoA/Rho-associated kinase and arginase are implicated in vascular complications in diabetes. This study investigated whether RhoA/Rho-associated kinase and arginase inhibition protect from myocardial ischaemia-reperfusion injury in type 1 diabetes and the mechanisms behind these effects.
Rats with streptozotocin-induced type 1 diabetes and non-diabetic rats were subjected to 30 min myocardial ischaemia and 2 h reperfusion after being randomized to treatment with (1) saline, (2) RhoA/Rho-associated kinase inhibitor hydroxyfasudil, (3) nitric oxide synthase inhibitor N-monomethyl-l-arginine monoacetate followed by hydroxyfasudil, (4) arginase inhibitor N-omega-hydroxy-nor-l-arginine, (5) N-monomethyl-l-arginine monoacetate followed by N-omega-hydroxy-nor-l-arginine or (6) N-monomethyl-l-arginine monoacetate given intravenous before ischaemia.
Myocardial arginase activity, arginase 2 expression and RhoA/Rho-associated kinase activity were increased in type 1 diabetes ( p < 0.05). RhoA/Rho-associated kinase inhibition and arginase inhibition significantly reduced infarct size in diabetic and non-diabetic rats ( p < 0.001). The cardioprotective effects of hydroxyfasudil and N-omega-hydroxy-nor-l-arginine in diabetes were abolished by nitric oxide synthase inhibition. RhoA/Rho-associated kinase inhibition attenuated myocardial arginase activity in diabetic rats via a nitric oxide synthase-dependent mechanism.
Inhibition of either RhoA/Rho-associated kinase or arginase protects from ischaemia-reperfusion injury in rats with type 1 diabetes via a nitric oxide synthase-dependent pathway. These results suggest that inhibition of RhoA/Rho-associated kinase and arginase constitutes a potential therapeutic strategy to protect the diabetic heart against ischaemia-reperfusion injury.
RhoA/ Rho相关激酶和精氨酸酶与糖尿病血管并发症有关。本研究调查了抑制RhoA/ Rho相关激酶和精氨酸酶是否能预防1型糖尿病患者的心肌缺血-再灌注损伤以及这些作用背后的机制。
将链脲佐菌素诱导的1型糖尿病大鼠和非糖尿病大鼠随机分为以下几组进行治疗：（1）生理盐水组；（2）RhoA/ Rho相关激酶抑制剂法舒地尔组；（3）一氧化氮合酶抑制剂N-单甲基-L-精氨酸单乙酸盐随后给予法舒地尔组；（4）精氨酸酶抑制剂N-ω-羟基-L-精氨酸组；（5）N-单甲基-L-精氨酸单乙酸盐随后给予N-ω-羟基-L-精氨酸组；（6）在缺血前静脉给予N-单甲基-L-精氨酸单乙酸盐组。然后对大鼠进行30分钟心肌缺血和2小时再灌注。
1型糖尿病大鼠心肌精氨酸酶活性、精氨酸酶2表达和RhoA/ Rho相关激酶活性增加（p < 0.05）。抑制RhoA/ Rho相关激酶和精氨酸酶可显著降低糖尿病和非糖尿病大鼠的梗死面积（p < 0.001）。一氧化氮合酶抑制可消除法舒地尔和N-ω-羟基-L-精氨酸在糖尿病中的心脏保护作用。抑制RhoA/ Rho相关激酶可通过一氧化氮合酶依赖性机制减弱糖尿病大鼠心肌精氨酸酶活性。
抑制RhoA/ Rho相关激酶或精氨酸酶可通过一氧化氮合酶依赖性途径预防1型糖尿病大鼠的缺血-再灌注损伤。这些结果表明，抑制RhoA/ Rho相关激酶和精氨酸酶构成了一种潜在的治疗策略，可保护糖尿病心脏免受缺血-再灌注损伤。
