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May 14, 2019 e965 Zilong Li, BS Yong Xu, PhD In Response: We thank Dr Wang for his letter concerning our recently published article1 and appreciate the opportunity to respond to his comments. We agree with Dr Wang that mechanisms other than those proposed in our article could account for reactive oxygen species (ROS) production in the reperfused heart. Whereas megakaryocytic leukemia 1 (MKL1)–dependent activation of PERP (p53 apoptosis effector related to PMP-22) transcription primarily serves to promote apoptosis rather than ROS generation, endothelin induction by MKL1 may indeed lead to accelerated ROS production. Endothelin is selectively expressed by endothelial cells. We have reported that macrophage MKL1, but not cardiomyocyte MKL1, is essential for cardiac ROS generation and consequently ischemia-reperfusion injury; whether MKL1 derived from other cell populations (eg, endothelial cells) may play a role in this process is an open question awaiting further investigation. We have previously shown that MRTF-A (myocardin-related transcription factor A) is critically linked to pivotal pathophysiological events in the vascular endothelium by upregulation of adhesion molecules (eg, ICAM-1 [intercellular adhesion molecule 1]) and concomitant downregulation of endothelial nitric oxide synthase expression. Weng et al2 have shown MKL1 depletion in the endothelium protects from pressure overload– induced cardiac hypertrophy in mice, although it remains undetermined whether the protective effects were attributed to ROS attenuation. This issue certainly deserves further scrutiny. It has been clearly authenticated that excessive inflammation is blamed for a wide range of cardiovascular diseases, and more convincing evidence has shown there is attenuated tissue injury or ROS production when recruitment of leukocytes is blocked. Several inflammatory stimulants (eg, tumor necrosis factor-α, interleukin-1β, interferon-γ) may act on NOX2 (NADPH oxidase 2)–positive cells (eg, polymorphonuclear cells) after ischemia-reperfusion to induce ROS production. In our previous work, we revealed that MKL1, subjected to the modulation of an acetylation-deacetylation switch, orchestrates a proinflammatory agenda in macrophages.3 It is tempting to speculate that MKL1 might serve as a critical part in the regulation of ROS production in cardiac ischemia-reperfusion injury induced by inflammatory stimulants. We observed that administration of CCG-1423 for up to 3 weeks did not cause any adverse cardiac effects in mice.1 In addition, recent reports suggest that MKL1 deletion4 or pharmaceutical inhibition5 does not impair renal structure or function in mice. Although we agree that the utmost precaution should be exercised if and when MKL1 is targeted for the treatment of cardiac reperfusion injury in humans, current evidence suggests that MKL1 deficiency can be well compensated and tolerated and therefore is unlikely to be associated with unintended side effects. © 2019 American Heart Association, Inc. RESPONSE TO LETTER TO THE EDITOR