Restoration of Adiponectin-Connexin43 Signaling Mitigates Myocardial Inflammation and Dysfunction in Diabetic Female Rats.
Restoration of Adiponectin-Connexin43 Signaling Mitigates Myocardial Inflammation and Dysfunction in Diabetic Female Rats.
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DOI：
10.1097/fjc.0000000000000789
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发表时间：
2020-03
影响因子：
3
通讯作者：
Abdel-Rahman AA
中科院分区：
文献类型：
--
作者：
Leffler KE;Abdel-Rahman AA
我们的临床前研究结果重复了女性对2型糖尿病（T2 DM）诱发的心功能不全的超敏反应，沿着雌激素（E2）依赖性破坏心脏脂联素（APN）-连接蛋白43（Cx43）信号传导。后一种分子异常是否是女性心血管健康问题的基础仍然未知。我们假设，在糖尿病雌性大鼠中，破坏的APN-Cx43信号传导的恢复加重了这种性别/E2依赖性心功能不全。为了验证这一假设，我们使用脂联素受体1（AdipoR 1）激动剂AdipoRon雌性假手术（SO）和卵巢切除（OVX）大鼠，分别在高脂饮食和低剂量链脲佐菌素方案下表现出和缺乏T2 DM左心室（LV）功能障碍;非糖尿病对照SO和OVX大鼠接受对照饮食和链脲佐菌素载体。在T2 DM SO大鼠LV功能障碍中，AdipoRon减轻：（i）LV肥大，（ii）缩短分数（FS），LV发展压力，dP/dtmax，dP/dtmin和Tau降低。在相同大鼠的LV组织中，AdipoRon逆转了Cx43的降低和TNFα、血红素加氧酶1（HO-1）和循环心血管危险因子非对称二甲基精氨酸（ADMA）的升高。研究结果还揭示了AdipoRon的卵巢激素独立效应，其中包括抑制促氧化酶HO-1。这些新的发现产生了新的见解，在E2依赖性超敏反应T2 DM诱发的心脏炎症和功能障碍中，受损的APN-Cx43信号转导的因果作用。同样重要的是，研究结果确定了Cx43信号的恢复作为一种可行的治疗方式，以减轻这种妇女的心血管健康相关的问题。
Our preclinical findings replicated women’s hypersensitivity to type-2 diabetes mellitus (T2DM)-evoked cardiac dysfunction along with demonstrating estrogen (E2)-dependent disruption of the cardiac adiponectin (APN)-connexin43 (Cx43) signaling. Whether the latter molecular anomaly underlies this women’s cardiovascular health problem remains unknown. We hypothesized that restoration of the disrupted APN-Cx43 signaling alleviates this sex/E2-dependent cardiac dysfunction in diabetic female rats. To test this hypothesis, we administered the adiponectin receptor 1 (AdipoR1) agonist AdipoRon (30 mg/kg/d for 10 days) to female sham operated (SO) and ovariectomized (OVX) rats, which exhibited and lacked the T2DM left ventricular (LV) dysfunction, respectively, when fed high fat diet and received low dose streptozotocin regimen; non-diabetic control SO and OVX rats received control diet and vehicle for streptozotocin. In T2DM SO rats LV dysfunction, AdipoRon mitigated: (i) LV hypertrophy, (ii) reductions in fractional shortening (FS), LV developed pressure, dP/dtmax, dP/dtmin, and Tau. In LV tissues of the same rats, AdipoRon reversed reduction in Cx43 and elevations in TNFα, heme-oxygenase 1 (HO-1) and circulating cardiovascular risk factor Asymmetric Dimethylarginine (ADMA). The findings also revealed ovarian hormones independent effects of AdipoRon, which included dampening of the pro-oxidant enzyme HO-1. These novel findings yield new insight into a causal role for compromised APN-Cx43 signaling in the E2-dependent hypersensitivity to T2DM-evoked cardiac inflammation and dysfunction. Equally important, the findings identify restoration of Cx43 signaling as a viable therapeutic modality for alleviating this women’s cardiovascular health related problem.
影响因子：
3.3
作者：
Tomicek NJ;Hunter JC;Machikas AM;Lopez V;Korzick DH
通讯作者：
Korzick DH