Various cardiovascular pathologies are associated with vascular smooth muscle cell (VSMC) hypertrophy and elevated plasma leptin levels. We used the rat portal vein (RPV) cultured for three days to investigate the effect of mechanical stretch on autocrine secretion of leptin and the effect of exogenous leptin (3.1 nM) on VSMC. Stretching the RPV significantly up-regulated leptin production by greater than 100-fold and leptin receptor expression by up to 10-fold. In addition, stretch increased tissue weight by 23 Ϯ 1.3 and 30 Ϯ 1% (P Ͻ 0.05), respectively, in the absence or presence of leptin, although this was significantly attenuated by an antileptin antibody (166 ng/ ml). Unstretched RPV weight decreased by 7.5 Ϯ 1.8% in the absence of leptin, whereas in the presence of leptin, weight increased by 6.5 Ϯ 1.8% (P Ͻ 0.05). VSMC size and [ 3 H]leucine incorporation rates were significantly increased by leptin in stretched and unstretched tissues. Leptin-induced hypertrophy was associated with significant extracellular signal-regulated kinase (ERK1/2) activation as well as increased expression of angiotensinogen, the angiotensin type 1 receptor as well as preproendothelin-1, and the endothelin type A receptor, whereas ERK inhibition or inhibition of either the angiotensin II or endothelin-1 systems at both the synthesis and receptor levels blocked the hypertrophic response. The effects of leptin were also completely blocked by the cholesterol-chelating agent methyl-␤-cyclodextrin. Therefore, our study demonstrates stretch-dependent leptin release and a direct hypertrophic effect of leptin on RPV, the latter likely dependent on intact cholesterol-rich membrane microdomains and locally produced paracrine factors.

Leptin, the 16-kDa peptide hormone product of the ob gene, is produced primarily by adipocytes and was initially thought to exert its effects exclusively through actions on the hypothalamus via distinct leptin receptors termed OB-R. However, recent data show that leptin is produced elsewhere and that receptors are present in many other tissues. Using real-time PCR, we determined whether leptin and its receptors are present in the rat heart and demonstrated regional distribution patterns and gender differences as well as the effect of ischemia and reperfusion. Gene expression of leptin and its receptors (OB-Ra, OB-Rb, and OB-Re) was identified in myocytes and whole heart homogenates from all regions of the heart of male and female rats, with the highest abundance in left and right atria of male and female rats, respectively. No differences in regional distribution of OB-R were evident in male rat hearts. In female rats, expression was highest in right atria for all three isoforms and was significantly greater than in male rats. Ischemia and reperfusion significantly downregulated leptin and OB-R expression, although this was more pronounced in male rat hearts. Leptin release in the coronary effluent was also detected using ELISA, although this was generally unaffected by global ischemia and reperfusion. Our results demonstrate for the first time the presence of the leptin system, including the peptide and its receptors, in all regions of the rat heart. In view of emerging evidence for cardiac effects of leptin, it is proposed that the heart is a target for leptin action and that the peptide modulates function through a paracrine- or autocrine-dependent manner.

Real-world prescriptions do not reflect reported values, which suggests that other factors influence patient-physician decision-making around OAC therapy. Data on self-reported adherence to OAC therapy and discordance in the use of OACs from prescribed regimens are concerning and warrant further investigation.

Adipokines represent a family of proteins released by adipocytes that affect various biological processes including metabolism, satiety, inflammation, and cardiovascular function. The first adipokine to be identified is leptin, a product of the obesity gene whose primary function is to act as a satiety factor. However, it is now recognized that leptin and many of the newly discovered adipokines produce effects on numerous organ systems including the heart. Indeed, various adipokines including leptin, adiponectin, and apelin exert potent and diverse cardiovascular effects which are mediated by their specific receptors and involve complex and multifaceted cell-signalling pathways. Among these are effects on the heart as well as blood pressure where leptin has been proposed to potentially contribute to obesity-related hypertension. In this review, we focus primarily on the diverse effects of adipokines on the heart and discuss the potential cell-signalling mechanisms underlying their actions. The potential role of adipokines in the regulation of cardiac metabolism and function is discussed. Discussion is also presented on the emerging role, both deleterious and salutary, of various adipokines in heart disease with an examination of the possible underlying mechanisms which contribute to these effects.

No abstract