Beta1 integrins modulate beta-adrenergic receptor-stimulated cardiac myocyte apoptosis and myocardial remodeling.
Sympathetic nerve activity increases in the heart during cardiac failure. Here, we hypothesized that beta1 integrins play a protective role in chronic beta-adrenergic receptor-stimulated cardiac myocyte apoptosis and heart failure. L-isoproterenol (iso; 400 microg/kg per hour) was infused in a group of wild-type (WT) and beta1 integrin heterozygous knockout (hKO) mice. Left ventricular structural and functional remodeling was studied at 7 and 28 days of iso-infusion. Western blot analysis demonstrated reduced beta1 integrin levels in the myocardium of hKO-sham. Iso-infusion increased heart weight:body weight ratios in both groups. However, the increase was significantly higher in WT-iso. M-mode echocardiography indicated increased left ventricular end-diastolic diameter, percentage of fractional shortening, and ejection fraction in the WT-iso group. The percentage of fractional shortening and ejection fraction were significantly lower in hKO-iso versus hKO-sham and WT-iso. Peak left ventricular developed pressure and left ventricular end-diastolic pressure measured using Langendorff-perfusion analyses were significantly higher in the WT-iso group (P<0.05 versus WT-sham and hKO-Iso). The number of TUNEL-positive myocytes was significantly higher in hKO-iso hearts 7 and 28 days after iso-infusion. The increase in myocyte cross-sectional area and fibrosis was higher in the WT-iso group. Matrix metalloproteinase-9 protein levels were significantly higher in WT-iso, whereas matrix metalloproteinase-2 levels were increased in hKO-iso hearts. Iso-infusion increased phosphorylation of c-Jun N-terminal kinase and extracellular signal-regulated kinase 1/2 in both groups. The increase in c-Jun N-terminal kinase phosphorylation was significantly higher in hKO-iso (P<0.001 versus WT-iso). Thus, beta1 integrins play a crucial role in beta-adrenergic receptor-stimulated myocardial remodeling with effects on cardiac myocyte hypertrophy, apoptosis, and left ventricular function.
Krishnamurthy
Prasanna
P
Department of Physiology, James H. Quillen College of Medicine, James H. Quillen Veterans Affairs Medical Center, East Tennessee State University, Johnson City, 37614, USA.
Subramanian
Venkateswaran
V
Singh
Mahipal
M
Singh
Krishna
K
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D002303:Cardiac Output, Low / Q000000981:diagnostic imaging / Q000201:enzymology / Q000503:physiopathology*; D004452:Echocardiography; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation / Q000187:drug effects; D011312:Pressure; D013318:Stroke Volume / Q000187:drug effects; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
D000318:Adrenergic beta-Agonists; D019012:Integrin beta1; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D007545:Isoproterenol