Caloric Restriction Stimulates Revascularization in Response to Ischemia via Adiponectin-mediated Activation of Endothelial Nitric-oxide Synthase

Abstract

Caloric restriction (CR) can extend longevity and modulate the features of obesity-related metabolic and vascular diseases. However, the functional roles of CR in regulation of revascularization in response to ischemia have not been examined. Here we investigated whether CR modulates vascular response by employing a murine hindlimb ischemia model. Wild-type (WT) mice were randomly divided into two groups that were fed either ad libitum (AL) or CR (65% of the diet consumption of AL). Four weeks later, mice were subjected to unilateral hindlimb ischemic surgery. Body weight of WT mice fed CR (CR-WT) was decreased by 26% compared with WT mice fed AL (AL-WT). Revascularization of ischemic hindlimb relative to the contralateral limb was accelerated in CR-WT compared with AL-WT as evaluated by laser Doppler blood flow and capillary density analyses. CR-WT mice had significantly higher plasma levels of the fat-derived hormone adiponectin compared with AL-WT mice. In contrast to WT mice, CR did not affect the revascularization of ischemic limbs of adiponectindeficient (APN-KO) mice. CR stimulated the phosphorylation of endothelial nitric-oxide synthase (eNOS) in the ischemic limbs of WT mice. CR increased plasma adiponectin levels in eNOS-KO mice but did not stimulate limb perfusion in this strain. CR-WT mice showed enhanced phosphorylation of AMP-activated protein kinase (AMPK) in ischemic muscle, and administration of AMPK inhibitor compound C abolished CR-induced increase in limb perfusion and eNOS phosphorylation in WT mice. Our observations indicate that CR can promote revascularization in response to tissue ischemia via an AMPK-eNOS-dependent mechanism that is mediated by adiponectin.Obesity is closely associated with the development of metabolic syndrome and type 2 diabetes (1), which contribute to microvascular rarefaction and impaired collateral vessel growth under ischemic conditions (2-4). These conditions lead to increased vulnerability to ischemic injury and impaired wound healing and promote the progression of cardiovascular diseases. Thus, therapeutic approaches that enhance revascularization could be beneficial for ischemic vascular disease.Caloric restriction (CR) 4 has been shown to extend the life span of multiple species by retarding the aging process (5). In obese subjects CR has been shown to reduce visceral fat accumulation and also decrease body weight (6). CR have also been reported to lead to a reduction of hyperglycemia and hyperlipidemia that are major risk factors for ischemic heart diseases (7-12). A number of experimental studies have shown that CR attenuates atherosclerotic lesion formation (11), pathological cardiac hypertrophy (13), and ischemia-induced myocardial damage (14). These findings suggest that CR counteracts the unfavorable features of obese complications. However, the consequences of CR on vascular responses to tissue ischemia have not been examined.Adipose tissue secretes a variety of bioactive molecules, referred to as adipokines, that directly affect obesity-linked disord...

Adiponectin and Cardiovascular Disease

“…95 CR also enhances recovery of blood flow in response to limb ischemia in WT mice, accompanied by increased levels of eNOS phosphorylation and plasma adiponectin. 96 The stimulatory actions of CR on revascularization and eNOS phosphorylation of ischemic limbs are abolished in APN-KO mice, and, furthermore, CR does not improve blood flow recovery in the ischemic limbs of eNOS-KO mice. 96 Thus, CR promotes revascularization in response to tissue ischemia via an AMPK-eNOS-dependent mechanism that is mediated by adiponectin.…”

“…96 The stimulatory actions of CR on revascularization and eNOS phosphorylation of ischemic limbs are abolished in APN-KO mice, and, furthermore, CR does not improve blood flow recovery in the ischemic limbs of eNOS-KO mice. 96 Thus, CR promotes revascularization in response to tissue ischemia via an AMPK-eNOS-dependent mechanism that is mediated by adiponectin. Collectively, nutritional approaches aimed at increasing adiponectin production could be useful in the treatment of cardiovascular diseases.…”

NFAT/Fas signaling mediates the neuronal apoptosis and motor side effects of GSK-3 inhibition in a mouse model of lithium therapy

“…Lithium-treated mice lost 10%-15% of their body weight over the 8-week treatment described above. To control for lithium-induced decreases in body weight, a weight-matched group was maintained by means of caloric restriction similar to that described previously (77,78). Briefly, we first measured the daily amount of chow taken by an equivalent group of untreated mice for 1 week.…”

Pathways for Ischemic Cytoprotection: Role of Sirtuins in Caloric Restriction, Resveratrol, and Ischemic Preconditioning

“…Rats subjected to chronic intermittent fasting after myocardial ischemia induction were more likely to survive, showed reductions in infarct size, and had increased expression of antiapoptotic proteins (Katare et al, 2009). Furthermore, CR upregulated angiogenic factors and increased capillary density after myocardial ischemia (Katare et al, 2009) and was also shown to accelerate revascularization in mice after hindlimb ischemia (Kondo et al, 2009). Some evidence suggests SIRT1 may have an important role in the ability of CR to provide protection against ischemia.…”