Abdominal Aortic aneurysm (AAA) results in very high mortality upon rupture. To date, besides surgical intervention ?with only 10% of patients eligible-, no alternative therapeutic approaches are available. Therefore, it would be of high significance to identify novel strategies to effectively treat or prevent AAA in vivo. Vascular smooth muscle cells (VSMCs) are crucial in maintaining vascular wall integrity and function and VSMC homeostasis is disrupted in AAA. Transcription factor-EB (TFEB) is a ?master? regulator of lysosomal biogenesis and autophagy. However, the role of TFEB in VSMC functions and AAA formation remain to be explored. We demonstrated that TFEB inhibits apoptosis, MMP2/9 activity and inflammation in VSMCs. VSMC specific TFEB knockout (KO) significantly aggravates vascular wall matrix degradation in a mouse AAA model. Nitroalkene derivatives of fatty acids such as oleic (OA-NO2) and linoleic acid (LNO2) have profound protective effects against cardiovascular and metabolic diseases. Conjugated linoleic acid (CLA) was identified as the preferential and major nitrated endogenous fatty acid and is readily bioavailable in humans and experimental models upon oral delivery of CLA and inorganic nitrite (NO2), making it an attractive intervention for CVD. We found that nitro-CLA protects against AAA formation in the Ang II-induced AAA mouse model and inhibits VSMC inflammation and apoptosis in a TFEB-dependent manner. It also promotes TFEB nuclear translocation in vitro in an H148-dependent fashion suggesting that TFEB is a direct target of nitro-CLA. Based on these evidences, we will test the central hypothesis that activation of TFEB by enhancing the endogenous production of nitro-CLA protects against AAA formation through inhibition of VSMC dysfunction. By taking advantage of our unique animal models generated specifically for these studies and the combined expertise of the assembled team, we propose 3 aims.
Aim 1 : Characterize the protective role of VSMC TFEB in AAA formation. We will test our working sub-hypothesis that VSMC TFEB protects against AAA formation through inhibition of VSMC dysfunction.
Aim 2 : Determine that activation of TFEB by nitro-CLA inhibits VSMC dysfunction in vitro. The working sub-hypothesis is that nitro-CLA prevents VSMC dysfunction in a TFEB-dependent manner.
Aim 3 : Define TFEB as a novel therapeutic target for nitro-CLA inhibition of AAA formation in vivo. The working sub- hypothesis is that endogenous production of nitro-CLA protects against AAA formation through activation of VSMC TFEB. In summary, we will characterize the protective role of TFEB in AAA formation and establish nitro-CLA as a novel therapeutic strategy against AAA by targeting VSMC TFEB. This mechanistic research will set a solid foundation for rapid translation into clinical utilization of nitro-CLA and may lead to a breakthrough for treatment or/and prevention of AAA.
Abdominal Aortic aneurysm (AAA) is a life-threatening vascular disease and no alternative therapeutic approaches are available. The successful implementation of this proposal will define TEFB as a novel target of nitro-CLA and establish the feasibility for oral delivery of nitrite and CLA for physiological production of endogenous nitro-CLA as a novel pharmacological approach in prevention and/or treatment of AAA.