Xiaoyin Wang

Donor Myocardial Infarction Impairs the Therapeutic Potential of Bone Marrow Cells by an Interleukin-1–Mediated Inflammatory Response

Inflammation after myocardial infarction may explain failure of bone marrow cells to improve cardiac function in infarcted recipient hearts. Getting to the Heart of Bone Marrow Therapy If arteries are the highways of the body, arterial blockage is like a jackknifed tractor-trailer: It blocks the flow of traffic and prevents passage. However, whereas a traffic accident may merely delay your commute, arterial blockage can result in the death of nutrient- and oxygen-starved cells that are no longer fed by the blood, such as happens with a myocardial infarction (MI). In rodent models, cells from the bone marrow can substantially improve cardiac function after MI, but attempts to translate these studies into humans have met with limited success. Now, Wang et al. show that this failure in humans may result from inflammation caused by the MI itself and that blocking inflammation with an inhibitor of the cytokine IL-1 restored the healing power of the bone marrow cells. The difference in outcomes observed in the two systems stemmed from the purity of the mouse system. Because genetically identical mice are readily available, healthy littermates supply more than enough donor bone marrow cells to successfully repair damaged heart tissue. Humans, however, are not quite so uniform. Donor cells had to come from the patients themselves in order to prevent rejection or graft-versus-host disease. Wang et al. hypothesized that bone marrow cells from MI patients would be different from those of healthy donors. To better mimic the human situation, the authors used donor bone marrow cells from mice that suffered MI and found that these cells were also hindered in their ability to repair cardiac function after MI. However, anti-inflammatory treatment of the donor, including inhibition IL-1, restored the ability of these cells to fix cardiac function. This reverse-translation study, which took a clinical observation and attempted to explain it in a rodent model, has not only provided insight into the local environment after MI; it also suggests a new option for successfully treating MI in the clinic. Preventing or reversing the proinflammatory change in the bone marrow cells may help them to cause a change of heart. Delivery of bone marrow cells (BMCs) to the heart has substantially improved cardiac function in most rodent models of myocardial infarction (MI), but clinical trials of BMC therapy have led to only modest improvements. Rodent models typically involve intramyocardial injection of BMCs from distinct donor individuals who are healthy. In contrast, autologous BMCs from individuals after MI are used for clinical trials. Using BMCs from donor mice after MI, we discovered that recent MI impaired BMC therapeutic efficacy. MI led to myocardial inflammation and an increased inflammatory state in the bone marrow, changing the BMC composition and reducing their efficacy. Injection of a general anti-inflammatory drug or a specific interleukin-1 inhibitor to donor mice after MI prevented this impairment. Our findings offer an explanation of why human trials have not matched the success of rodent experiments and suggest potential strategies to improve the success of clinical autologous BMC therapy.

One Minute of Marijuana Secondhand Smoke Exposure Substantially Impairs Vascular Endothelial Function

Background Despite public awareness that tobacco secondhand smoke (SHS) is harmful, many people still assume that marijuana SHS is benign. Debates about whether smoke‐free laws should include marijuana are becoming increasingly widespread as marijuana is legalized and the cannabis industry grows. Lack of evidence for marijuana SHS causing acute cardiovascular harm is frequently mistaken for evidence that it is harmless, despite chemical and physical similarity between marijuana and tobacco smoke. We investigated whether brief exposure to marijuana SHS causes acute vascular endothelial dysfunction. Methods and Results We measured endothelial function as femoral artery flow‐mediated dilation (FMD) in rats before and after exposure to marijuana SHS at levels similar to real‐world tobacco SHS conditions. One minute of exposure to marijuana SHS impaired FMD to a comparable extent as impairment from equal concentrations of tobacco SHS, but recovery was considerably slower for marijuana. Exposure to marijuana SHS directly caused cannabinoid‐independent vasodilation that subsided within 25 minutes, whereas FMD remained impaired for at least 90 minutes. Impairment occurred even when marijuana lacked cannabinoids and rolling paper was omitted. Endothelium‐independent vasodilation by nitroglycerin administration was not impaired. FMD was not impaired by exposure to chamber air. Conclusions One minute of exposure to marijuana SHS substantially impairs endothelial function in rats for at least 90 minutes, considerably longer than comparable impairment by tobacco SHS. Impairment of FMD does not require cannabinoids, nicotine, or rolling paper smoke. Our findings in rats suggest that SHS can exert similar adverse cardiovascular effects regardless of whether it is from tobacco or marijuana.

Brief Exposure to Secondhand Smoke Reversibly Impairs Endothelial Vasodilatory Function

INTRODUCTION We sought to determine the effects of brief exposures to low concentrations of tobacco secondhand smoke (SHS) on arterial flow-mediated dilation (FMD, a nitric oxide-dependent measure of vascular endothelial function), in a controlled animal model never before exposed to smoke. In humans, SHS exposure for 30 min impairs FMD. It is important to gain a better understanding of the acute effects of exposure to SHS at low concentrations and for brief periods of time. METHODS We measured changes in FMD in rats exposed to a range of real-world levels of SHS for durations of 30 min, 10 min, 1 min, and 4 breaths (roughly 15 s). RESULTS We observed a dose-response relationship between SHS particle concentration over 30 min and post-exposure impairment of FMD, which was linear through the range typically encountered in smoky restaurants and then saturated at higher concentrations. One min of exposure to SHS at moderate concentrations was sufficient to impair FMD. CONCLUSIONS Brief SHS exposure at real-world levels reversibly impairs FMD. Even 1 min of SHS exposure can cause reduction of endothelial function.

Overexpression of Nitric Oxide Synthase Restores Circulating Angiogenic Cell Function in Patients With Coronary Artery Disease: Implications for Autologous Cell Therapy for Myocardial Infarction

Background Circulating angiogenic cells (CACs) are peripheral blood cells whose functional capacity inversely correlates with cardiovascular risk and that have therapeutic benefits in animal models of cardiovascular disease. However, donor age and disease state influence the efficacy of autologous cell therapy. We sought to determine whether age or coronary artery disease (CAD) impairs the therapeutic potential of CACs for myocardial infarction (MI) and whether the use of ex vivo gene therapy to overexpress endothelial nitric oxide (NO) synthase (eNOS) overcomes these defects. Methods and Results We recruited 40 volunteers varying by sex, age (< or ≥45 years), and CAD and subjected their CACs to well‐established functional tests. Age and CAD were associated with reduced CAC intrinsic migration (but not specific response to vascular endothelial growth factor, adherence of CACs to endothelial tubes, eNOS mRNA and protein levels, and NO production. To determine how CAC function influences therapeutic potential, we injected the 2 most functional and the 2 least functional CAC isolates into mouse hearts post MI. The high‐function isolates substantially improved cardiac function, whereas the low‐function isolates led to cardiac function only slightly better than vehicle control. Transduction of the worst isolate with eNOS cDNA adenovirus increased NO production, migration, and cardiac function of post‐MI mice implanted with the CACs. Transduction of the best isolate with eNOS small interfering RNA adenovirus reduced all of these capabilities. Conclusions Age and CAD impair multiple functions of CACs and limit therapeutic potential for the treatment of MI. eNOS gene therapy in CACs from older donors or those with CAD has the potential to improve autologous cell therapy outcomes.

Advanced Donor Age Impairs Bone Marrow Cell Therapeutic Efficacy for Cardiac Disease.

Therapeutic results of clinical autologous bone marrow cell (BMC) therapy trials for cardiac disease have been modest compared to results of BMC implantation into rodent hearts post-myocardial infarction (MI). In clinical trials, autologous BMCs are typically harvested from older patients who have recently suffered an MI. In contrast, experimental studies in rodent models typically utilize donor BMCs isolated from young, healthy, inbred mice that are not the recipients. Using unfractionated BMCs from donor mice at ages of young, middle-aged, and old, we discovered that recipient left ventricular function post-MI was significantly improved by young donor BMC implantation but was only preserved by middle-aged donor BMCs. Notably, old donor BMCs did not slow the decline in recipient post-MI cardiac function, suggesting BMC impairment by advanced donor age. Furthermore, we also show here that BMCs that are therapeutically impaired by donor age can be further impaired by concurrent donor MI. In conclusion, our findings suggest that therapeutic impairment of BMCs by advanced age is one of the important factors that can limit the success of clinical autologous BMC-based therapy.

Impairment of Endothelial Function by Little Cigar Secondhand Smoke.

OBJECTIVES Little cigars and cigarillos are gaining in popularity as cigarette use wanes, mainly due to relaxed regulatory standards that make them cheaper, easier to buy individually, and available in a variety of flavors not allowed in cigarettes. To address whether they should be regulated as strictly as cigarettes, we investigated whether little cigar secondhand smoke (SHS) decreases vascular endothelial function like that of cigarettes. METHODS We exposed rats to SHS from little cigars, cigarettes, or chamber air, for 10 minutes and measured the resulting acute impairment of arterial flow-mediated dilation (FMD). RESULTS SHS from both little cigars and cigarettes impaired FMD. Impairment was greater after exposure to little cigar SHS than by cigarette SHS relative to pre-exposure values, although the post-exposure FMD values were not significantly different from each other. CONCLUSIONS Exposure to little cigar SHS leads to impairment of FMD that is at least equal to that resulting from similar levels of cigarette SHS. Our findings support the need to prevent even brief exposure to little cigar SHS, and support tobacco control policies that regulate little cigars as strictly as cigarettes.

Blunting Half of the Double-Edged Sword: Potential Use of Interleukin–10 to Protect Bone Marrow-Derived Cells After Myocardial Infarction

See related article, pages 1280–1289 During a myocardial infarction (MI), tissue damage resulting from the ischemia and subsequent reperfusion injury triggers a complex combination of cellular responses,1 much of which is bone marrow–derived. Some of these responses involve a harmful inflammatory reaction to cytokines released by dying cardiomyocytes that can exacerbate the ongoing local structural damage. Other responses are beneficial, for example, the prohealing arm of the inflammatory response that replaces the necrotic and inflamed region with a fibrous scar. Still other beneficial effects are thought to be mediated by mobilized bone marrow cells (BMCs) of multiple lineages that aid in tissue healing.2,3 Much effort has gone into harnessing this endogenous cellular response by harvesting resident or mobilized bone marrow–derived cells and administering them to post-MI hearts,4–7 with the hope that the cells will regenerate myocardium via differentiation2,8 or will preserve at-risk myocardium by actively9 or passively10 releasing paracrine growth factors or secreting exosomes.11,12 However, the aforementioned inflammatory response can cause problems by creating an environment in the post-MI heart that may be inhospitable for naturally attracted and therapeutically administered BMCs alike. Moreover, the MI-induced inflammatory response transitions the BMCs themselves to a more proinflammatory state, interfering with their therapeutic abilities.13 In this issue of Circulation Research , Krishnamurthy and colleagues14 explore naturally occurring mechanisms of dampening the inflammatory response that could potentially augment the efficacy of cell therapy for MI. Their focus is on a particular subpopulation of BMCs, the endothelial progenitor cells (EPCs). These cells, which were originally discovered in rodents, …