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Foster Lab Awarded Grant from the American Heart Association

A few weeks ago we were thrilled to learn that the AHA has chosen to fund our work on altered retinoic acid homeostasis in heart failure progression with a Transformational Project Award. I wish to extend my thanks to the AHA, past and present members of the research team (Ni, Lauren & Kyriakos), as well as colleagues for their critical advice and support (you know who you are).

Foster Lab 2016 Year-in-Review Part I: The Book

Manual of Cardiovascular Proteomics coverYikes, it’s been a while since the last update. As we begin 2017, this is a good time to reflect on the year that was. A source of pride in 2016 was the publication of the book Manual of Cardiovascular Proteomics, which I co-edited with Dr. Giulio Agnetti Assistant Professor of Medicine and Director of the Center for Research on Cardiac Intermediate Filaments here at Johns Hopkins Cardiology, and Dr. Merry Lindsey, Professor of Physiology/Medicine and Director of the Mississippi Center for Heart Research at the University of Mississippi. It was a delight to work with them as well as the cadre of exceptional contributors that includes both icons of cardiovascular proteomics and emerging stars. Merry, Giulio and I also chipped in a few chapters ;-). The scope of the book is pretty impressive, ranging from the time-honored fundamentals of chromatography and mass spectrometry to the modern tools of statistics, pathway, and network analyses, as they are applied to hotbed fields including ischemia-reperfusion injury, heart failure, vascular dysfunction, stem cell biology and clinical biomarker development. Check it out.

Foster Lab 2016 Year-in-Review Part II: The Paper

image002In September 2016 we published the big one. I am referring to our paper:

Integrated Omic Analysis of a Guinea Pig Model of Heart Failure and Sudden Cardiac Death. J Proteome Res. 2016 Sep 2;15(9):3009-28. doi: 10.1021/acs.jproteome.6b00149. PMID: 27399916
in which we examined the transcriptome, proteome and metabolome of heart failure progression in a modified pressure-overload guinea pig model that uniquely recapitulates both the transition from compensated hypertrophy to end-stage heart failure, but also clinically relevant sudden cardiac death. The model was developed by Dr. Ting Liu and Dr. Brian O’Rourke, Professor of Medicine and Vice-Chair for Basic and Translational Research in the Department of Medicine at Johns Hopkins. This paper represents the culmination of a broad collaboration between cardiac physiologists and biochemists, MS specialists, bioinformaticists and statisticians and commercial partners.

The goal was more than to simply extensively phenotype a new model of heart failure. Rather, we used the latest inferential pathway and upstream regulator analyses to garner new insights into likely gene-regulatory programs at work both early in hypertrophy and upon cardiac decompensation. We also wanted to showcase the value of multi-omic integration. The transcriptome provided the greatest depth of coverage particularly for proteomically-recalcitrant proteins like ion channels and other integral membrane proteins. But the proteins are the ultimate executors of cardiac function and for nearly 3000 of them, the correlation between protein and transcript changes in heart failure was fairly weak and were sometimes diametrically opposed, suggesting substantial post-transcriptional regulation. By integrating the proteome and metabolome we were also able to identify putative bottlenecks in metabolism.

Along with Dr. O’Rourke and collaborators, we have laid out the multi-omic landscape of hypertrophy and heart failure and have distilled a few essential take home messages. Moreover, our hope is that this study will serve as a resource for the research community. Along with the article, we have included an expansive online supplement that contains reader-friendly tables of analyses, as well as raw MS2 signal intensities for those who wish mine the data further.


Journal plos 1 image

Publication of the Cardiac Acetyl-Lysine Proteome

Journal plos 1 imageOur most recent paper detailing the sites of lysine acetylation in the heart is now published in the online journal, PLOS One, and is also accessible through PubMed. One of the take home messages of the paper is that lysine acetylation in the heart goes beyond the well documented locations in the mitochondria and nucleus, and extends to  calcium-handling proteins of the sarcoplasmic reticulum and the sarcomere. We present novel acetylation sites and outline testable hypotheses by which lysine acetylation might modulate function of key proteins involved in excitation-contraction coupling.

20-year Quest Ends as Scientists Pin Down Structure of Elusive, Heart-protective Protein

Team led by Johns Hopkins investigators defines structure of the long-sought mitochondrial potassium channel, mitoKATP, which protects against muscle-damaging heart attacks

Public release date: 17-Jul-2012
Johns Hopkins Medical Institutions

It is a cellular component so scarce, some scientists even doubted its existence, and many others gave up searching for its molecular structure. Now a team led by researchers at Johns Hopkins has defined the protein structural composition of mitoKATP, a potassium channel in the mitochondria of the heart and other organs that is known to protect against tissue damage due to a heart attack or stroke. Importantly, the newly found channel strongly improves heart cell survival, demonstrating an essential life-saving role.

In a report to be published in the journal Circulation Research online July 17, the O’Rourke group and colleagues from Portland State University in Oregon describe their successful efforts to pinpoint and identify mitoKATP, which is an opening, or “pore,” responsible for potassium uptake into mitochondria, the powerhouses of the heart cell. This particular potassium channel is a key player in the heart’s intrinsic ability to protect itself from a loss of blood flow, speeding recovery from heart attacks and preventing cell death and scar tissue formation. Unexpectedly, the protein structure of mitoKATP matched that of another, much more plentiful and well-known potassium channel in the kidney, called ROMK.

Senior study investigator Brian O’Rourke, Ph.D., professor at the Johns Hopkins University School of Medicine’s Heart and Vascular Institute and director of the Bernard Laboratory of Fundamental Research in Preventive Cardiology, says the team’s discovery solves a 20-year mystery among cardiologists, physiologists and protein biochemists. Although there was abundant evidence that enhancing the ability of the mitochondria to take up potassium ions strongly protects against myocardial infarction, the channel behind this protective effect had escaped detection.

Noting that other scientists had failed to pin down mitoKATP among other known heart potassium channels and mitochondrial proteins, the Hopkins team broadened the search for new, presumably unknown heart mitochondrial proteins. Using cow hearts, chosen because their large size offered more mitochondrial starting material, lead author and protein biochemist, D. Brian Foster, Ph.D., used mass spectrometry to identify 20 million peptide signatures that yielded over 900 potential mitochondrial proteins — only one of which stood out as a tantalizing candidate for mitoKATP. Surprisingly, this candidate, ROMK, was a channel known to be found in the kidney, but had never been previously detected in mitochondria.

Foster and study co-lead investigator, Alice S. Ho, a Ph.D. candidate in biomedical engineering at Hopkins, then set up a series of experiments to determine if the mitochondrial version of ROMK (mitoROMK) was indeed a key component of mitoKATP and had similar heart protective qualities. Using cultured heart-derived cells, she showed that ROMK is localized to mitochondria. Next, Ho perfected an assay for mitoROMK activity, by monitoring mitochondrial uptake of thallium, which has a similar size and electrical charge as potassium. In cells in which mitoROMK was depleted, thallium uptake was decreased by more than 70 percent.

Additional supporting evidence came from experiments using Tertiapin Q, a honeybee toxin known to block ROMK. Co-investigator Keith Garlid, M.D., and his research team in Oregon, employing a classic assay for mitoKATP, showed that treating mitochondria with Tertiapin Q potently inhibited potassium-dependent mitochondrial swelling. The honeybee toxin also inhibited mitoKATP activity using the thallium assay.

A final set of experiments demonstrated mitoROMK’s protective effects in cells; increasing mitoROMK levels led to increased rat heart cell survival and less damage after exposure to increasing amounts of tert-butyl hydroperoxide, an oxidizing chemical that mimics heart attack, heart cells with depleted mitoROMK levels had a higher death rate with the same treatment.

O’Rourke says this study provides the first molecular key to unlocking the pore structure of the cardioprotective mitoKATP channel. More work will be required to fully understand the role of mitoROMK in protecting against cell injury and death in intact animals and humans during heart disease. However, since mitoROMK is expressed in organs such as the brain and liver too, the work uncovers a new avenue for therapies targeting mitochondria and opens the door for discovering more potent and specific drugs that activate mitoKATP.


Funding for the study was provided by the U.S. National Institutes of Health, specifically corresponding grant numbers P01-HL081427, R01-HL108917 and P01-HL36573.

In addition to O’Rourke, Foster and Ho, other researchers involved in this study were Jasma Rucker, B.S., Ling Chen, M.S., Agnieszka Sidor, Ph.D all at Johns Hopkins; and Anders Garlid, B.Sc. and Keith Garlid, M.D., Ph.D., at Portland State University, in Oregon.

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Contact: David March