Three recent studies address heart failure. One, a collaboration with Case Western Reserve University School of Medicine and University Hospitals in Cleveland, involves βARs and GPCRs signaling. The aim is to determine whether S-nitrosylation – a novel target – can be modulated or manipulated to prevent heart failure. In another, we showed that stopping the gene-regulating activity of GRK5 could help prevent cardiac hypertrophy secondary to chronic hypertension – revealing for the first time, in vivo, that keeping GRK5 out of the heart cell nucleus can block the abnormal growth process. This Katz School of Medicine study opens new avenues for the development of GRK5-based heart failure treatment. In a third cardiac hypertrophy study, Katz School of Medicine scientists were the first to show that a key transcription factor called FoxO1 activates a wide array of genes in heart cells, leading to widespread increases in growth signaling. The study was also the first to show, in vivo, that inhibiting FoxO1 expression in the heart prevents cardiac overgrowth caused by chronic hypertension, shedding light on an understudied mechanism of pathological heart growth.

In another line of investigation, recent work on processes that maintain the electrical and contractile properties of the heart (and defects that lead to arrhythmias, sudden death, and congestive heart failure) has focused on the determinants of the two major forms of human heart failure: heart failure with reduced and preserved ejection fraction (HFrEF and HFpEF). This original work suggests that structural and functional defects in HFpEF can be reversed with a drug that has previously been used successfully for cancer patients.

Katz scientists were also the first to identify Krϋppel-like factor KLF5 as a common mediator of cardiac damage in models of different diseases that lead to abnormal heart function, including diabetes.  The study identified KLF5 is a causative factor in the production of ceramides underlying heart-wall damage (as driven by KLF5-induced overexpression of a molecule known as SPT1). The findings expose KLF5 as a new target for different types of cardiac disease, opening novel avenues for treatment. 

Another recent study elucidated a previously unknown role of cardiac protein cJun N-terminal kinase (JNK) in sepsis, identifying a path to potential new therapy for this often-fatal condition. Katz scientists found that decreased cardiac output and hypotension in sepsis are closely associated with pathological production of B-type natriuretic peptide (BNP) – and that when BNP is decreased (by blocking JNK activation in the circulation), blood pressure stabilizes. In addition to opening a potential avenue to new therapy, this work points to the potential to target BNP as biomarker for the clinical assessment of sepsis – which could be a great boon to early diagnosis and intervention.

Abdominal aortic aneurysm is the topic of another recent study. Katz scientists shed new light on mitochondrial fission and fusion as an underlying contributing mechanism of this potentially deadly age-related condition. We showed, for the first time, in vivo, that using an inhibitor called mdivi1 to block dynamin-related protein 1 (Drp1) can halt the development of abdominal aortic aneurysm. We found that inhibiting Drp1 reduced stress responses in vascular cells -- lessening infiltration of inflammatory cells and decreasing cell senescence – all characteristic of by aging-related cellular deterioration. A Drp1 inhibitor may be the therapeutic answer to preventing abdominal aortic aneurysm for patients at risk.

The Department benefits from a longstanding support from the NIH, both for our core research and for specific training programs. For example, the Department has a prestigious Training Award supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health that funds several pre- and post-doctoral trainees in cardiovascular translational science.