Leptin augments coronary vasoconstriction and smooth muscle proliferation via a Rho-kinase-dependent pathway

Abstract

Leptin has been implicated as a key upstream mediator of pathways associated with coronary vascular dysfunction and disease. The purpose of this investigation was to test the hypothesis that leptin modifies the coronary artery proteome and promotes increases in coronary smooth muscle contraction and proliferation via influences on Rho kinase signaling. Global proteomic assessment of coronary arteries from lean swine cultured with obese concentrations of leptin (30 ng/mL) for 3 days revealed significant alterations in the coronary artery proteome (68 proteins) and identified an association between leptin treatment and calcium signaling/contraction (4 proteins) and cellular growth and proliferation (35 proteins). Isometric tension studies demonstrated that both acute (30 min) and chronic (3 day, serum-free media) exposure to obese concentrations of leptin potentiated depolarization-induced contraction of coronary arteries. Inhibition of Rho kinase significantly reduced leptin-mediated increases in coronary artery contractions. The effects of leptin on the functional expression of Rho kinase were time-dependent, as acute treatment increased Rho kinase activity while chronic (3 day) exposure was associated with increases in Rho kinase protein abundance. Proliferation assays following chronic leptin administration (8 day, serum-containing media) demonstrated that leptin augmented coronary vascular smooth muscle proliferation and increased Rho kinase activity. Inhibition of Rho kinase significantly reduced these effects of leptin. Taken together, these findings demonstrate that leptin promotes increases in coronary vasoconstriction and smooth muscle proliferation and indicate that these phenotypic effects are associated with alterations in the coronary artery proteome and dynamic effects on Rho kinase pathway.

Roles of sarcoplasmic reticulum Ca2+ ATPase pump in the impairments of lymphatic contractile activity in a metabolic syndrome rat model

“…Thus, we propose that increased intracellular Ca 2+ due to decreased SERCA2 expression and activity in LMCs of MetSyn animals lead to an increase in MLC 20 phosphorylation that causes a reduction in the diameter of lymphatic vessels and consequently, poor lymphatic function in MetSyn conditions that we previously reported 9 , 10 . Since Rho kinase regulates myosin light chain phosphatase (MLCP), which is one of the critical regulators of MLC 20 phosphorylation 64 , 65 and Rho kinase activity is increased in MetSyn condition 66 , 67 , we examined the phosphorylation levels of MYPT1, a subunit of MLCP, in insulin resistant LMCs. Results showed the relative levels of MYPT1 phosphorylation were not significantly changed in insulin resistant LMCs (Data not shown).…”

Cardiovascular consequences of metabolic syndrome

“…Roles of adipokines in the regulation of many relevant features of obesity-associated cardiovascular disease have been described, including effects of adipokines on insulin sensitivity (leptin, adiponectin and resistin), inflammation (IL-8, monocyte chemotactic protein 1, leptin, chemerin), coagulation (plasminogen activator inhibitor-1), and vascular function and atherosclerosis (leptin, resistin, tumor necrosis factor-alpha, adiponectin,visfatin, omentin). (24, 156-163) Relevant fat depots also include the fat on the heart itself. Cardiac adipose tissue volume expands with obesity, but accumulates preferentially around coronary arteries, and atherosclerotic plaques occur predominantly in arteries encased by perivascular adipose tissue (PVAT).…”

Epicardial Adipose Tissue Removal Potentiates Outward Remodeling and Arrests Coronary Atherogenesis

“…The contiguity of cEAT with coronary arterial adventitia without an intervening fibrous layer (2, 8, 17, 28) might also restrict outward dilation of the proximal conduit coronary artery during diastole. Alternatively, cEAT from obese Ossabaw pigs expresses and secretes vasoconstrictors (29–31) which when removed might result in tonic vasodilation. It cannot be determined from our work whether the expansion of the EEL is due to outward medial enlargement or to enhanced vasodilation.…”