Lab Research Interests

Our laboratory includes researchers with both basic science and clinical backgrounds.  We are interested in addressing clinical problems using preclinical models that have direct applicability to the understanding, prevention, and treatment of cardiovascular disease. 

Major interests:


Therapies for myocardial infarction and heart failure
Angiogenesis
Role of NO synthase in circulating angiogenic cell function
Vascular dysfunction by tobacco and marijuana secondhand smoke

(View smoking-related public service announcements in collaboration with the Elfenworks Foundation)


Therapies for myocardial infarction
and heart failure

We are studying the therapeutic effects of implanting bone marrow-derived cells (BMCs) into mouse hearts after myocardial infarction (MI), using a high-resolution echocardiography approach that we developed in collaboration with Dr. Yeghiazarians to guide injections into the myocardial wall without surgery.  The echo-guided approach allows us to introduce BMCs to mouse hearts several days after MI, a time relevant to current clinical trials that is not feasible when using traditional open-chest injection approaches.  We have shown that injection of BMCs 3 days post-MI can preserve or partially restore left ventricular function.  We have also demonstrated that injection of a cell-free extract of lysed BMCs has a similar therapeutic effect, suggesting not only that BMC therapy may be beneficial by a paracrine mechanism, but also that the cells may simply die and thus deliver a bolus of therapeutic growth factors. 

We and others have found BMC therapy to be quite effective at improving cardiac function post-MI in rodents, but human clinical trials of BMC therapy have been less robust.  We have recently demonstrated in mice that regardless of the state of the recipient heart, the donor BMCs themselves are therapeutically impaired by the age and post-MI state of the donor.  This is an important point because human bone marrow cell therapy trials are autologous; that is, the patients are treated with their own cells, and those cells are thus derived from older, post-MI individuals.  In contrast, mouse model BMC therapy experiments use bone marrow harvested from one mouse and delivered to the hearts of others, and the donor mice are typically younger and healthy, a poor reflection of the clinical situation being modeled.  We have shown that BMCs from old donor mice lack therapeutic efficacy for treatment of MI, and cells from donor mice that are themselves post-MI are impaired.  In the case of donor MI, the MI causes inflammation in the heart that changes the composition of the bone marrow via interleukin-1-mediated signaling such that the harvested BMCs are in a pro-inflammatory state.  This research was featured on the UCSF website in late 2011.

A recent major effort has focused on a fibrosis inhibitor as a potential treatment for post-MI heart failure.  Our preliminary results in rats are promising, and this section will be updated when results are published.


Angiogenesis 

We are interested in the responses of adult cardiac and skeletal muscle to angiogenic signaling and gene therapy, focusing on effects of VEGF on the vasculature.  This continues Dr. Springer's pre-UCSF research aimed at understanding the response of adult tissue to exogenous VEGF gene delivery, potential deleterious effects, and potential therapeutic applications.  We are also studying potential neovascularization effects of pleiotrophin, a less-characterized growth factor, which we have shown to be a chemoattractant for circulating angiogenic cells (otherwise known as endothelial progenitor cells).  In addition, we are currently studying myocardial-specific mechanisms of angiogenesis and how microvascular endothelial cells successfully carry out the required pattern formation while subjected to the cyclical compressive forces in the heart.


Role of NO synthase in human circulating angiogenic cell function

We are interested in the molecular basis of age- and disease-related impairment of circulating angiogenic cells (CACS; which have also been called early endothelial progenitor cells or EPCs), a heterogeneous population of cells that are thought to be involved in several aspects of angiogenesis and endothelial maintenance. 

We are studying endothelial nitric oxide synthase (eNOS)-dependent and eNOS-independent mechanisms of CAC migration toward angiogenic stimuli by VEGF and pleiotrophin, and are investigating the molecular mechanisms through which NO controls CAC migration and interactions with endothelium.  The contributions of inherent eNOS activity and oxidative stress to overall CAC function are being investigated, as are strategies to use eNOS gene therapy to modify their potential as therapeutic agents for cardiovascular disease.


Vascular dysfunction by tobacco and marijuana secondhand smoke

Flow-mediated vasodilation (FMD), the process by which arteries sense increased blood flow requirements, is important for maintaining cardiovascular health and a useful prognostic indicator.  We have developed a micro-ultrasound-based approach to measure FMD in arteries of living rats, and have shown that FMD in the rat model is physiologically similar to that in humans.  The vasodilation that occurs after transient upstream arterial occlusion is dependent on hyperemic blood flow and is also dependent on eNOS activity.  We have been able to detect age-related impairment of FMD with this approach, and have used this system to study the beneficial effects of modulation of NO bioavailability on endothelial function.

We are currently studying how vascular function is impaired by brief exposure to low levels of tobacco secondhand smoke through a range of real-world smoke concentrations, with impairment detectable after only one minute of exposure.  Our research is also addressing effects of smoke from alternative tobacco products such as little cigars and e-cigarettes.  We recently reported at the 2014 American Heart Association annual conference that exposure to marijuana secondhand smoke for 30 minutes (with most of the exposure occuring during the first 10 minutes) caused similar harmful effects to vascular function, even if the drug THC had been removed from the marijuana.  Taken together, our results indicate that to prevent harmful cardiovascular effects of secondhand smoke, it is not sufficient that public exposure is reduced, it should be prevented; and that secondhand smoke should be avoided whether it comes from tobacco or marijuana.  We feel that this kind of research is important because it uses lab-based approaches to directly influence public health, by providing information to the public and to government agencies and legislators about relative risks associated with exposure to smoke from different sources.

(View a 2/2013 talk at the UCSF Center for Tobacco Control Research and Education "It's About a Billion Lives" symposium for the general public about our studies; let it load and then move the slider to time 1:36:45; it is about 25 minutes long.)