Department of Emergency, The First Affiliated Hospital of China Medical University, 110001 Shenyang, Liaoning, China.
Front Biosci (Landmark Ed). 2023 Sep 27;28(9):231. doi: 10.31083/j.fbl2809231.
Diabetes mellitus type 2 is a risk factor for developing heart failure and myocardial fibrosis, but there is no specific therapy for diabetic heart disease. 1-[2-(4-methoxyphenyl)]-2-[3-(4-methoxyphenyl) propoxy]ethyl-1H-imidazole (SKF96365) is regarded as an inhibitor of receptor-mediated calcium ion (Ca2+) entry. This study aimed to explore the effects of SKF96365 on diabetic myocardial fibrosis.
A type 2 diabetic rat model induced by a high-sugar and high-fat diet combined with streptozotocin was established. Thirty specific pathogen-free male Wistar rats were divided randomly into three groups: group A (the blank control group), group B (the diabetes group) and group C (the diabetes + transient receptor potential canonical channel [TRPC] blocker intervention group). Group C was given 0.74-µmol/kg SKF96365 by intraperitoneal injection, and groups A and B were given the same amount of normal saline by intraperitoneal injection. The weight and blood sugar of the rats were monitored. After 12 weeks, the weight of the whole heart and the left ventricle was measured, and the heart and the left ventricular weight ratios were calculated. Haematoxylin-eosin (HE) staining was used to observe pathological changes in the myocardial tissue and the distribution of nuclei. Masson staining was used to identify collagen and muscle fibres, and the myocardial collagen volume fraction (CVF) was calculated. Semi-quantitative reverse transcription-polymerase chain reaction was used to detect the messenger ribonucleic acid (mRNA) expression of SKF96365 target genes. A value of 0.05 indicated that the difference between the groups was statistically significant.
Compared with the weight of the rats in group A, the weight of those in groups B and C decreased, while blood sugar, whole heart weight and left ventricular weight increased ( 0.05). There was no significant difference in body weight between the rats in groups B and C ( > 0.05). The HE staining results showed that the arrangement of cardiomyocytes in groups B and C was irregular, and focal necrosis was seen in severe cases. The degree of diabetic cardiomyopathy (DCM) in group C was less severe than that in group B. Masson staining showed that the CVF increased in groups B and C, with group B > group C ( < 0.05); the mRNA expressions of TRPC3 and TRPC6 were upregulated in groups A, B and C, and the mRNA expressions of TRPC3 and TRPC6 in group C were downregulated compared with those in group B ( < 0.05). Compared with the expression levels of SKF96365 target genes (, and ) in group A, those in group B were lower, while the administration of SKF96365 in group C did not affect the expression levels of those genes.
SKF96365 can effectively improve myocardial fibrosis in type-II diabetic rats.
2 型糖尿病是心力衰竭和心肌纤维化的危险因素，但目前尚无针对糖尿病性心脏病的特定疗法。1-[2-(4-甲氧基苯基)]-2-[3-(4-甲氧基苯基)丙氧基]乙基-1H-咪唑（SKF96365）被认为是一种受体介导热离子（Ca2+）内流的抑制剂。本研究旨在探讨 SKF96365 对糖尿病性心肌纤维化的影响。
采用高糖高脂饮食联合链脲佐菌素诱导 2 型糖尿病大鼠模型。将 30 只特定病原体无特定病原体雄性 Wistar 大鼠随机分为 3 组：A 组（空白对照组）、B 组（糖尿病组）和 C 组（糖尿病+瞬时受体电位经典通道[TRPC]阻断剂干预组）。C 组给予 0.74-µmol/kg SKF96365 腹腔注射，A、B 组给予等量生理盐水腹腔注射。监测大鼠体重和血糖。12 周后，测量大鼠全心重和左心室重，并计算心脏和左心室重量比。苏木精-伊红（HE）染色观察心肌组织的病理变化和核的分布。Masson 染色鉴定胶原和肌纤维，计算心肌胶原容积分数（CVF）。半定量逆转录聚合酶链反应检测 SKF96365 靶基因的信使核糖核酸（mRNA）表达。P<0.05 表示组间差异有统计学意义。
与 A 组大鼠体重相比，B、C 组大鼠体重下降，血糖、全心重和左心室重增加（P<0.05）。B、C 组大鼠体重比较差异无统计学意义（P>0.05）。HE 染色结果显示，B、C 组大鼠心肌细胞排列不规则，严重者可见局灶性坏死。C 组糖尿病心肌病（DCM）程度较 B 组轻。Masson 染色显示，B、C 组 CVF 增加，B 组> C 组（P<0.05）；A、B、C 组 TRPC3 和 TRPC6 的 mRNA 表达均上调，C 组 TRPC3 和 TRPC6 的 mRNA 表达均低于 B 组（P<0.05）。与 A 组 SKF96365 靶基因（、和）的表达水平相比，B 组的表达水平较低，而 C 组给予 SKF96365 并不影响这些基因的表达水平。
SKF96365 可有效改善 2 型糖尿病大鼠的心肌纤维化。
