Ivan Luptak, MD, PhD
|Institution||Boston University School of Medicine|
|Address||650 Albany St Evans Biomed Research Ctr|
|2015||-||2020||American Heart Association:
Fellow to Faculty Transition Award|
Metabolic syndrome is a cluster of obesity-related metabolic abnormalities that affects an estimated 34% of the U.S. population and increases the risk of developing cardiovascular disease, including metabolic heart disease (MHD). MHD, which is characterized by left ventricular (LV) hypertrophy and impaired diastolic relaxation, culminates in diastolic heart failure. Currently there is no specific therapy for diastolic heart failure. We made a novel observation that a diet high in fat and sucrose (HFHS) leads to MHD and causes an abnormal increase in the intracellular concentration of sodium (Na) in the heart. It’s known that elevated cytosolic Na may deplete mitochondrial calcium and lead to both decreased ATP and increased damaging reactive oxygen species (ROS) production.
We hypothesize that elevated myocardial Na leads to impaired mitochondrial calcium signaling in MHD. As result, mitochondria produce less ATP and more ROS. Consequently, less ATP is available to fuel cell functions such as relaxation and contraction. Of the two, myocardial relaxation is more susceptible to the lack of ATP, thus diastolic dysfunction ensues.
To test our hypothesis, we will use mice fed HFHS diet that become obese and develop MHD. Our aims will test 1) the role of Na elevation in decreased ATP and increased ROS production, 2) the role of Na-induced decreased ATP production in energetic and contractile dysfunction and 3) the role of Na-induced increased ROS production in mediating MHD.
To address these aims, intracellular Na, mitochondrial calcium and mitochondrial ROS will be manipulated in vitro and ex vivo using a variety of pharmacologic and transgenic interventions. Mitochondrial function and ROS production will be assessed in isolated mitochondria, calcium regulation and function will be assessed in isolated myocytes, and cardiac intracellular Na and energetics will be assessed in beating hearts using 23Na and 31P NMR spectroscopy.
- energetic metabolism
- NMR spectroscopy
- heart failure
- intracellular sodium
- diastolic dysfunction
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