Fenofibrate promotes ischemia-induced revascularization through the adiponectin-dependent pathway

Abstract

Recent clinical trials demonstrated that PPAR␣ agonist fenofibrate reduces cardiovascular events, including limb amputation in people with type 2 diabetes. Here, we investigated whether fenofibrate modulates the revascularization process in a mouse model of hindlimb ischemia. Treatment with fenofibrate led to acceleration of revascularization of ischemic hindlimb relative to the contralatereal limb in wild-type (WT) mice, as measured by laser Doppler blood flow and capillary density analyses. Treatment of WT mice with fenofibrate increased the serum levels of adiponectin, which has protective actions on the vasculature. Of importance, fenofibrate had no effects on the revascularization in ischemic limbs of adiponectin-deficient (APN-KO) mice. Fenofibrate stimulated the phosphorylation of AMPK and eNOS in the ischemic muscles in WT mice but not in APN-KO mice. AMPK inhibitor compound C suppressed fenofibrate-induced increase in limb perfusion and AMPK phosphorylation in ischemic muscle in WT mice without affecting adiponectin levels. NOS inhibitor L-NAME also blocked the increased blood flow of ischemic limbs in fenofibratetreated WT mice. Our observations suggest that fenofibrate could promote revascularization in response to ischemia through adiponectin-dependent AMPK signaling.angiogenesis; endothelial nitric oxide synthase

Energy intake and adiponectin gene expression

“…Although there is a relatively low abundance of PPAR␣ in WAT compared with brown adipose and liver in mice, the direct regulatory roles of PPAR␣ in gene expression and energy metabolism have been clearly identified in WAT (18,20,37,41). Consistent with previous studies (16,21,22,26,38), our study reveals that PPAR␣ agonist stimulates adiponectin gene expression in cultured adipocytes (Fig. 5A).…”

“…Within the PPAR family, PPAR␥ is probably best known for increasing circulating adiponectin levels by upregulating adiponectin expression at the transcriptional level (24). Interestingly, significantly increased blood adiponectin concentrations were also observed in PPAR␣ agonist-treated human subjects and animal models (16,21,22,26,38). In addition, an in vitro experiment has demonstrated that PPAR␣ directly increases adiponectin gene transcription through the peroxisome proliferator response elements (PPRE) at the adiponectin promoter (16).…”

Current role of fenofibrate in the prevention and management of non-alcoholic fatty liver disease

“…PPARα activation appears to play a key role in these benefits of adiponectin; thus fenofibrate exhibited the same properties [91,92] . Also, clinical and experimental studies showed that fenofibrate increases adiponectin plasma levels [93,94] . This was associated with vascular benefits of the drug and the rise in HDL-C levels [93,94] .…”

“…Also, clinical and experimental studies showed that fenofibrate increases adiponectin plasma levels [93,94] . This was associated with vascular benefits of the drug and the rise in HDL-C levels [93,94] . Except for adiponectin, its liver-specific R2 receptor (AdipoR2) appears to play a role in steatosis and inflammation.…”

Systemic administration of ghrelin did not restore angiogenesis in hindlimb ischemia in control and diet-induced obese mice

“…Then, an incision was made in the skin overlying the middle portion of the left hindlimb. The femoral artery and its associated branches and vein were isolated, ligated and excised (15). The animals were followed up for next 48 h. Then, the mice were randomly assigned to one of the following experimental groups: control and obese groups treated with ghrelin, control and obese groups received vehicle (n = 6 each group).…”