Research Article: Cardioprotective effects of PKG activation by soluble GC activator, BAY 60-2770, in ischemia-reperfusion-injured rat hearts

Date Published: July 3, 2017

Publisher: Public Library of Science

Author(s): Kyung Hye Lee, So-Ra Lee, Haneul Cho, Jong Shin Woo, Jung Hee Kang, Yun-Mi Jeong, Xian Wu Cheng, Woo-Shik Kim, Weon Kim, John Calvert.


Soluble guanylate cyclase (sGC) has been suggested as a therapeutic target for cardiac ischemia-reperfusion (IR) injury. Until now, the molecular mechanism of BAY 60–2770, a sGC activator, in cardiac IR injury has not been assessed. To identify the cardioprotective effects of BAY 60–2770 in IR-injured rat hearts, IR injury was established by occlusion of LAD for 40 min and reperfusion for 7 days, and the effects of BAY 60–2770 on myocardial protection were assessed by echocardiography and TTC staining. 5 nM and 5 μM of BAY 60–2770 were perfused into isolated rat hearts in a Langendorff system. After 10- or 30-min reperfusion with BAY 60–2770, cGMP and cAMP concentrations and PKG activation status were examined. Hearts were also perfused with 1 μM KT5823 or 100 μM 5-HD in conjunction with 5 nM Bay 60–2770 to evaluate the protective role of PKG. Mitochondrial oxidative stress was investigated under hypoxia-reoxygenation in H9c2 cells. In IR-injured rat hearts, BAY 60–2770 oral administration reduced infarct size by TTC staining and improved left ventricular function by echocardiography. Tissue samples from BAY 60-2770-perfused hearts had approximately two-fold higher cGMP levels. BAY 60–2770 increased PKG activity in the myocardium, and the reduced infarct area by BAY 60–2770 was abrogated by KT-5823 in isolated myocardium. In H9c2 cardiac myoblasts, hypoxia-reoxygenation-mediated mitochondrial ROS generation was diminished with BAY 60–2770 treatment, but was recovered by pretreatment with KT-5823. BAY 60–2770 demonstrated a protective effect against cardiac IR injury via mitoKATP opening and decreased mitoROS by PKG activation. BAY 60–2770 has a protective effect against cardiac IR injury via mitoKATP opening and decreased mitoROS by PKG activation. These results demonstrated that BAY 60–2770 may be used as a therapeutic agent for cardiac IR injury.

Partial Text

Myocardial ischemic-reperfusion (IR) injury is induced through quick restoration of blood flow, resulting in robust reactive oxygen species (ROS) generation and damage or dysfunction of the cardiac tissue [1]. IR-injured cardiac myocytes have some limitations under pathological conditions, including reduced nitric oxide (NO) generation and oxidized heme in soluble guanylate cyclase (sGC). sGC is an important enzyme in the cardiovascular system and is expressed in vascular endothelial cells [2], smooth muscle cells [3] and cardiac myocytes [4, 5]. sGC stimulators such as YC-1 and BAY 41–2272 trigger the generation of cyclic 3’,5-guanosine monophosphate (cGMP) without NO binding [6, 7]. sGC activators target NO-insensitive oxidized, heme-free sGC, which protects sGC from proteasomal degradation [8].

Cardiac IR injury increased mitochondrial oxygen radical production and further enhanced oxidative cellular damage. Increased generation of ROS has been suggested to be a major contributor to the pathogenic mechanisms of cell death and cardiac IR injury [19]. Mitochondrial ROS generation and mitochondrial matrix Ca2+ overload converge to induce opening of the mitochondrial permeability transition pore [17]. Therefore, reducing mitochondrial ROS production upon reperfusion is an appealing therapeutic target for minimizing IR injury. Because IR injury has pathological conditions that reduce NO generation and oxidize heme in sGC, several sGC activators have been developed and used as agents to protect against IR injury.




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