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:

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 using this approach to study how vascular function is impaired by brief exposure to low levels of 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 (including JUUL), and we have recently reported that aerosol from the current generation of so-called "heat-not-burn" tobacco products (such as IQOS) impairs vascular function comparably to tobacco smoke.  We have shown that exposure to marijuana secondhand smoke for even one minute causes similar harmful effects to vascular function, even if the cannabinoids, including the drug THC, have 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 also recently demonstrated that substances in the blood of people who use e-cigarettes can directly interfere with the ability of cultured endothelial cells to produce nitric oxide, which is an important molecule for proper vascular health.  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.


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.  (This research was featured on the UCSF website in late 2011.)  In the case of donor MI, the MI causes IL-1-mediated inflammation in the heart that changes the composition of the bone marrow such that the harvested BMCs are in a pro-inflammatory state, which includes containing a reduced number of B lymphocytes.  Most recently, we have shown that the B lymphocytes themselves are responsible for at least much of the therapeutic activity of the BMCs, and that cell-free extract of lysed B lymphocytes is therapeutic.

We have also demonstrated that post-MI human bone marrow cells from patients are also therapeutically impaired, confirming that our mouse results are relevant to the clinical situation. 

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.


View a 5/2/18 seminar (UCSF Cardiology Grand Rounds) that was an overview of the current research in the lab; it's about an hour long.

View a 9/24/19 seminar (Stanford University Cardiovascular Institute Frontiers series) of the science and policy aspects of our tobacco and marijuana research; 47 minutes.

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

CornerMingXiaoyinHuiliang

 

Ronak

 

Jiangtao, Pooneh

 

 
Lab view