西地那非治疗周围动脉疾病

    西地那非通过依赖通路促进局部缺血引起的血管生成，从而有治疗周围动脉疾病的作用。周围动脉疾病是一种常见的心血管疾病，可导致严重肢体局部缺血。通过刺激慢性缺血部位的动脉血管生成仍是治疗周围动脉疾病的重要治疗手段。动物实验证明，西地那非抑制磷酸二脂酶5的活性可增加慢性局部缺血部位肌肉灌注、组织血流和血管密度。其作用机制是通过PKG依赖通路实现的。

Sildenafil Promotes Ischemia-Induced Angiogenesis Through a PKG-Dependent Pathway

Annamalai Senthilkumar, Ray D. Smith, Jayant Khitha, Neeraj Arora, Srikar Veerareddy, Will Langston, John H. Chidlow Jr, Shayne C. Barlow, Xinjun Teng, Rakesh P. Patel, David J. Lefer, and Christopher G. Kevil. Arteriosclerosis, Thrombosis, and Vascular Biology. Published Online ，on June 21, 2007

Background--Peripheral artery disease (PAD) is a prevalent cardiovascular disorder that results in tissue ischemia which can progress to critical limb ischemia. Restoration of tissue perfusion in the setting of chronic ischemia through stimulation of arteriogenesis and angiogenesis remains a key therapeutic target for PAD. However, experimental therapeutics, including growth factor and gene therapy, have had little clinical success indicating the need for a better understanding of molecular pathways required for therapeutic angiogenesis.

Methods and Results--Here we report that phosphodiesterase-5 inhibition by sildenafil significantly increases vascular perfusion, tissue blood flow, and vascular density during chronic ischemia of the mouse hind limb. Importantly, sildenafil therapy did not alter any of these parameters in nonischemic limbs. Sildenafil increased tissue cGMP levels independently of increases in nitric oxide production, and sildenafil therapy stimulated angiogenesis in ischemic limbs of eNOS^-/- and iNOS^-/- mice. Lastly, sildenafil-mediated angiogenic activity was blocked by inhibition of protein kinase G using the PKG antagonist DT-3.

Conclusions--These data demonstrate that sildenafil therapy results in increased angiogenic activity through a PKG-dependent pathway that is independent of nitric oxide production or NOS activity and identify the angiogenic therapeutic potential of sildenafil for critical limb ischemia.

    解读：

    蛋白激酶G(Protein Kinase G,PKG)。

    PKG也称为cGMP依赖性激酶(CGK)，是cGMP信号通路的主要受体和介导物质。一氧化氮合酶(NOS)催化底物后生成NO，NO与可溶性鸟苷酸环化酶结合，促使GTP转化成cGMP，再激活cGMP依赖性的蛋白激酶(PKG)，使蛋白质磷酸化而发挥生物学效应，即NOS/NO/cGMP/PKG作用通路。