Suppression of AVIC inflammosteogenesis for prevention of CAVD progression

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 DESCRIPTION (provided by applicant): Calcific aortic valve disease (CAVD) is a leading cardiovascular disorder in the elderly. Currently, pharmacological intervention for slowing down or halting the progression of this disease is unavailable. Our recent studies found that human aortic valve interstitial cells (AVICs) express both inflammatory and osteogenic mediators in response to pro-inflammatory stimulation and display up-regulates pro-osteogenic activity characterized by elevated levels of alkaline phosphatase (ALP) and the formation of calcification nodules. Characterization of diseased aortic valves revealed the accumulation of oxLDL in valvular tissue and reduced levels of IL-37 (an anti-inflammatory cytokine) in AVICs. Preliminary studies found that oxLDL induces AVIC expression of ALP via TLR2 and TLR4, and that IL-37 is potent in suppression of AVIC inflammosteogenic responses. Importantly, expression of IL-37 in mice attenuates obesity, hyperlipidemia and aortic valve lesions caused be high fat diet. We formulated two interrelated Aims for this project. Specific Aim 1 is to test the hypothesis that IL 37 suppresses the inflammosteogenic responses in human AVICs. We will pursue the following sub aims: A) to test the hypothesis that IL-37 deficiency in AVICs affected by CAVD augments the inflammosteogenic responses to risk factors; B) to determine the mechanism of IL-37 deficiency in AVICs of diseased human aortic valves; C) to examine the interaction of inflammatory mediators with osteogenic mediators in up-regulation of AVIC osteogenic activity; D) to test the hypothesis that recombinant IL-37 suppresses the osteogenic activity (ALP expression/activity and calcium deposit formation) in AVICs of diseased aortic valve; E) to test the hypothesis that IL-37 inhibits IRAK1 to suppress ERK1/2/NF-kB activation and the inflammosteogenic responses in human AVICs. Specific Aim 2 is to determine the effect of IL-37 on aortic valve lesions in mice fed with high fat diet. We will pursue the following sub aims: A) t test the hypothesis that TLR2/4 and IRAK1 play a critical role in mediating aortic valve lesions caused by high fat diet; B) to determine the effect of recombinant IL-37 on hyperlipidemia and aortic valve lesions caused by high fat diet; C) to determine the effect of expression of IL-37 on hyperlipidemia and aortic valve lesions caused by high fat diet. These studies will provide insights into the molecular mechanism by which risk factors induce valvular cell pro-osteogenic reprogramming. In addition, these studies will identify potential therapeutic targets for suppression of the progression of CAVD.