糖尿病心肌梗死后易发心力衰竭的新机制：心肌钠尿肽抵抗

Diabetes is the most important risk factor of myocardial infarction (MI) and heart failure (HF). The risk of HF after MI in diabetics is markedly higher than in non-diabetics. However, the underlying mechanisim is largely unknown. We previously confirmed that the death rate, deterioration of heart function, and the ventricular remodeling of type 2 diabetic mice were more serious compared with the non-diabetic control after ligation of ramus descendens anterior arteriae coronariae sinistrae. In addition, our preliminary experiments found that the levels of plasma natriuretic peptides were aberrantly elevated in the rats with diabetes mellitus type 2, accompanied with deterioration of NPRA-cGMP-PKG signaling pathway of natriuretic peptides in the myocardium, which was alleviated by insulin treatment. It suggests that the dysfunction of insulin signal possibly results in natriuretic peptide resistance in myocardium, which might be culpable for the predisposition to HF after the MI in diabetes mellitus. Using type 2 diabetic rats and mice with conditionally knocked-out insulin receptor (InsR) in myocardium, the current study is to investigate the changes of natriuretic peptide signals as well as its relation to the insulin signals on the condition that insulin signals are dysregulated. Moreover, mice with conditionally knocked-out natriuretic peptide receptor NPRA in myocardium are to be used to evaluate the vulnerability to acute ischemia as well as the susceptibility to chronic ischemic HF, on the condition that the natriuretic peptide signaling pathway is defected. The present study is supposed to find a novel mechanism underlying the predisposition to HF after the MI in diabetes mellitus. Also, this project will give clues about efficient methods and targets against diabetic ischemic HF.

糖尿病已成为心肌梗死（心梗）和心力衰竭（心衰）最重要的危险因素，糖尿病患者心梗后发生心衰的危险性远高于非糖尿病患者，但其机制不明。我们前期证实2型糖尿病小鼠心梗后的死亡率、心功能恶化及心室重构的速度均较非糖尿病对照显著。申请人预实验还发现，糖尿病状态下的血浆钠尿肽水平异常升高，并伴有心肌NPRA-cGMP-PKG钠尿肽信号通路受损，且胰岛素治疗后显著改善。提示糖尿病状态下的胰岛素信号异常可能导致心肌钠尿肽抵抗，这可能是糖尿病心梗后易发心衰的重要机制。本课题拟采用2型糖尿病大鼠和心肌条件性敲除胰岛素受体InsR的小鼠，研究胰岛素信号异常时心肌钠尿肽信号的变化规律，及其与胰岛素信号之间的关系。进而，采用心肌条件性敲除钠尿肽受体NPRA的小鼠，在钠尿肽信号通路缺陷的情况下，观察心肌的缺血耐受性和慢性缺血性心衰易感性的变化。旨在揭示糖尿病心梗后易发心衰的新机制，为防治糖尿病性缺血性心衰提供新思路。

糖尿病已经成为心肌梗死（心梗）和心力衰竭（心衰）最重要的危险因素。糖尿病心肌梗死后易发心衰，但其机制不明。本研究采用2型糖尿病小鼠，给予心肌缺血处理，发现2型糖尿病小鼠心梗后的死亡率、心功能恶化及心室重构的速度均较非糖尿病对照显著，且血浆钠尿肽水平异常升高，并伴有心肌NPRA-cGMP-PKG信号通路受损。提示有“糖尿病性心肌钠尿肽抵抗”发生。类似的，高糖/高脂培养的H9c2心肌细胞，cGMP/PKG信号减弱，外源性钠尿肽BNP的干预，可以有效抑制LDH和CK释放，减轻缺氧/再给氧的高糖/高脂培养的H9c2心肌细胞凋亡，抑制内质网应激，从而对心肌细胞起到保护作用。进而，采用心肌条件性敲除钠尿肽受体NPRA的小鼠，人为破坏钠尿肽信号通路，观察了心肌的缺血耐受性和慢性缺血性心衰易感性的变化。本研究揭示了糖尿病心梗后易发心衰的新机制，为从提高钠尿肽敏感性角度防治糖尿病性缺血性心衰提供了新的思路。