Dr Timothy O'Connell

Integrative Biology/Physiology
Medical School
Twin Cities
Project Title: 
Ffar4 in Heart failure

This laboratory focuses on G-protein coupled receptor (GPCR) signaling in the heart, with two main areas of emphasis:

  • Free fatty acid receptor 4 (Ffar4): Ffar4 is a G-protein coupled receptor for long chain fatty acids (Carbon chains 14-24) including omega-3 polyunsaturated fatty acids (w3-PUFAs). Clinically, w3-PUFAs improve outcomes in heart failure, but the mechanism is unclear. This group has previously demonstrated that eicosapentaenoic acid, or EPA an w3-PUFA, prevents heart failure in a mouse model but not through the traditional mechanism of membrane incorporation. Alternatively, they found that the cardioprotective effects of EPA might be mediated through Ffar4, an entirely novel molecular mechanism to explain the benefits of w3-PUFAs in the heart. Currently, this research is focused on understanding this novel role for Ffar4 as a cardioprotective nutrient sensor in the heart that responds to fatty acid composition to protect the heart from pathologic stress.
  • a1-Adrenergic receptors (a1-AR): a1-ARs are receptors activated by the endogenous sympathetic catecholamines norepinephrine (produced in sympathetic nerve terminals) and epinephrine (produced in the adrenal gland). Clinically, a1-ARs were originally used for the treatment of hypertension (HTN) and are currently used to treat benign prostatic hyperplasia (BPH). Clinical trials demonstrated that a1-AR antagonists (doxazosin) worsened outcomes in patients with HTN, significantly increasing cardiac events and doubling the risk of heart failure. This work has provided a mechanistic basis to explain the failure of a1-blockers in patients with HTN, demonstrating that a1-ARs in cardiac myocytes protect the heart from pathologic stress. Currently, this research is focused on understanding the molecular basis for the cardioprotective effects of a1-ARs focusing on how differential subcellular compartmentalization of receptors affects their function. Further, based on their work on a1-AR subcellular compartmentalization, the researchers are developing a next-generation a1-blocker for HTN without cardiac side-effects.

Project Investigators

Dr. Juan Abrahante - Llorens
Katherine Murphy
Megin Nguyen
Dr Timothy O'Connell
 
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