Leptin’s regulation of obesity-induced cardiac extracellular matrix remodeling

Abstract

Obesity-induced remodeling of cardiac extracellular matrix (ECM) leads to myocardial fibrosis and ultimately diastolic dysfunction. Leptin, an adipocyte hormone, is emerging as a novel mechanistic link between obesity and heart diseases. Despite the known essential role of leptin in hepatic and renal fibrosis, the in vivo effects of leptin on cardiac ECM remodeling remain unclear. Our objective was to define the role of leptin as a key mediator of pro-fibrogenic responses in the heart. In vitro administration of leptin to primary cardiofibroblasts resulted in significant stimulation of pro-collagen Iα ( 1 ) and a decrease in pro-matrix metalloproteinase (MMP)-8, -9 and -13 gene expressions at 24 h. To study the in vivo pro-fibrotic effect, leptin was administrated to C57BL/6 and leptin-deficient ob/ob mice for 8 weeks. With exogenous leptin ob/ob mice displayed passive diastolic filling dysfunction, coincided with significant increase in myocardial collagen compared with ob/ob controls. We also observed a marked stimulation of pro-collagen IIIα ( 1 ) and suppression of pro-MMP-8, TIMP-1 and -3 gene expressions in leptin-treated ob/ob mice. Our findings suggest pro-fibrotic effects of leptin in the heart, primarily through the predominance of collagen synthesis over degradation.

Maternal Cardiovascular Impairment in Pregnancies Complicated by Severe Fetal Growth Restriction

“…19 In particular, the metabolic effects of obesity resulting in dyslipidemia and insulin resistance seem to be the most likely mediators of changes in maternal cardiac function through changes in the composition and material properties of the myocardium. [19][20][21][22][23][24] This assertion is indirectly supported by a recent study demonstrating that Ϸ20% of women who previously had a normotensive FGR pregnancy had features of metabolic syndrome. 25 The endothelial dysfunction is another known mechanism of diastolic impairment 26 and could also play a role in the diastolic abnormalities seen in normotensive FGR, as well as PE pregnancies.…”

Adipocyte-Derived Hormone Leptin Is a Direct Regulator of Aldosterone Secretion, Which Promotes Endothelial Dysfunction and Cardiac Fibrosis

“…In the present study we focused on the effects of leptin on endothelial dysfunction, a major precursor and contributor of cardiovascular disease and a key feature of obesity, 1,40,49 and on cardiac fibrosis, another characteristic of the obese phenotype and major precursor to heart failure, atrial arrhythmias, and sudden cardiac death. 50,51 We reported for the first time that both leptin-mediated endothelial dysfunction 49 and leptin-associated increases in cardiac fibrotic markers 50 involve mineralocorticoid receptors activation. Indeed, mineralocorticoid receptors antagonism with spironolactone prevented the reduction in endothelium-dependent relaxation induced by chronic leptin treatment.…”

“…Similarly, we showed that mineralocorticoid receptors antagonism prevented leptin-induced increases in the expression of collagen 1α1, collagen 3α1, and periostin, three profibrotic markers. This suggests that leptin-induced cardiac fibrosis 50,51 involves mineralocorticoid receptor-dependent mechanisms. Together these data present leptin-mediated increases in aldosterone as a detrimental mechanism for the cardiovascular system and as a major risk factor for cardiovascular disease in the obese population.…”

Obesity, metabolic dysfunction, and cardiac fibrosis: pathophysiological pathways, molecular mechanisms, and therapeutic opportunities

“…Whether fibroblast-specific effects of leptin mediate myocardial fibrosis in obesity has not been rigorously tested. However, exogenous leptin administration in ob/ob mice significantly increased myocardial collagen content promoting matrix-preserving actions (110). …”