{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T03:38:05Z","timestamp":1789616285017,"version":"build-2803163510"},"reference-count":57,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2010,11,12]]},"abstract":"<jats:sec>\n            <jats:title>\n              <jats:underline>Rationale:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>Mechanotransduction and the response to biomechanical stress is a fundamental response in heart disease. Loss of phosphoinositide 3-kinase (PI3K)\u03b3, the isoform linked to G protein\u2013coupled receptor signaling, results in increased myocardial contractility, but the response to pressure overload is controversial.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Objective:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>To characterize molecular and cellular responses of the PI3K\u03b3 knockout (KO) mice to biomechanical stress.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Methods and Results:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>In response to pressure overload, PI3K\u03b3KO mice deteriorated at an accelerated rate compared with wild-type mice despite increased basal myocardial contractility. These functional responses were associated with compromised phosphorylation of Akt and GSK-3\u03b1. In contrast, isolated single cardiomyocytes from banded PI3K\u03b3KO mice maintained their hypercontractility, suggesting compromised interaction with the extracellular matrix as the primary defect in the banded PI3K\u03b3KO mice. \u03b2-Adrenergic stimulation increased cAMP levels with increased phosphorylation of CREB, leading to increased expression of cAMP-responsive matrix metalloproteinases (MMPs), MMP2, MT1-MMP, and MMP13 in cardiomyocytes and cardiofibroblasts. Loss of PI3K\u03b3 resulted in increased cAMP levels with increased expression of MMP2, MT1-MMP, and MMP13 and increased MMP2 activation and collagenase activity in response to biomechanical stress. Selective loss of N-cadherin from the adhesion complexes in the PI3K\u03b3KO mice resulted in reduced cell adhesion. The \u03b2-blocker propranolol prevented the upregulation of MMPs, whereas MMP inhibition prevented the adverse remodeling with both therapies, preventing the functional deterioration in banded PI3K\u03b3KO mice. In banded wild-type mice, long-term propranolol prevented the adverse remodeling and systolic dysfunction with preservation of the N-cadherin levels.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Conclusions:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>The enhanced propensity to develop heart failure in the PI3K\u03b3KO mice is attributable to a cAMP-dependent upregulation of MMP expression and activity and disorganization of the N-cadherin\/\u03b2-catenin cell adhesion complex. \u03b2-Blocker therapy prevents these changes thereby providing a novel mechanism of action for these drugs.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.110.229054","type":"journal-article","created":{"date-parts":[[2010,9,17]],"date-time":"2010-09-17T04:32:09Z","timestamp":1284697929000},"page":"1275-1289","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":51,"title":["Loss of PI3K\u03b3 Enhances cAMP-Dependent MMP Remodeling of the Myocardial N-Cadherin Adhesion Complexes and Extracellular Matrix in Response to Early Biomechanical Stress"],"prefix":"10.1161","volume":"107","author":[{"given":"Danny","family":"Guo","sequence":"first","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine (D.G., F.L.C., G.Y.O.); Mazankowski Alberta Heart Institute (D.G., Z.K., R.B., F.L.C., V.K., G.Y.O.); and Department of Physiology (Z.K., R.B., V.K., G.Y.O.), University of Alberta, Edmonton, Canada; University of Torino (F.D., E.H.), Italy; Department of Physiology (W.L., P.H.B.), University of Toronto, Canada; Beth Israel Deaconess Medical Center (S.I.), Harvard Medical School, Boston Mass; and Institute of Molecular Biotechnology of the..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zamaneh","family":"Kassiri","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine (D.G., F.L.C., G.Y.O.); Mazankowski Alberta Heart Institute (D.G., Z.K., R.B., F.L.C., V.K., G.Y.O.); and Department of Physiology (Z.K., R.B., V.K., G.Y.O.), University of Alberta, Edmonton, Canada; University of Torino (F.D., E.H.), Italy; Department of Physiology (W.L., P.H.B.), University of Toronto, Canada; Beth Israel Deaconess Medical Center (S.I.), Harvard Medical School, Boston Mass; and Institute of Molecular Biotechnology of the..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ratnadeep","family":"Basu","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine (D.G., F.L.C., G.Y.O.); Mazankowski Alberta Heart Institute (D.G., Z.K., R.B., F.L.C., V.K., G.Y.O.); and Department of Physiology (Z.K., R.B., V.K., G.Y.O.), University of Alberta, Edmonton, Canada; University of Torino (F.D., E.H.), Italy; Department of Physiology (W.L., P.H.B.), University of Toronto, Canada; Beth Israel Deaconess Medical Center (S.I.), Harvard Medical School, Boston Mass; and Institute of Molecular Biotechnology of the..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fung L.","family":"Chow","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine (D.G., F.L.C., G.Y.O.); Mazankowski Alberta Heart Institute (D.G., Z.K., R.B., F.L.C., V.K., G.Y.O.); and Department of Physiology (Z.K., R.B., V.K., G.Y.O.), University of Alberta, Edmonton, Canada; University of Torino (F.D., E.H.), Italy; Department of Physiology (W.L., P.H.B.), University of Toronto, Canada; Beth Israel Deaconess Medical Center (S.I.), Harvard Medical School, Boston Mass; and Institute of Molecular Biotechnology of the..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay","family":"Kandalam","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine (D.G., F.L.C., G.Y.O.); Mazankowski Alberta Heart Institute (D.G., Z.K., R.B., F.L.C., V.K., G.Y.O.); and Department of Physiology (Z.K., R.B., V.K., G.Y.O.), University of Alberta, Edmonton, Canada; University of Torino (F.D., E.H.), Italy; Department of Physiology (W.L., P.H.B.), University of Toronto, Canada; Beth Israel Deaconess Medical Center (S.I.), Harvard Medical School, Boston Mass; and Institute of Molecular Biotechnology of the..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Damilano","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine (D.G., F.L.C., G.Y.O.); 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and Institute of Molecular Biotechnology of the..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seigo","family":"Izumo","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine (D.G., F.L.C., G.Y.O.); Mazankowski Alberta Heart Institute (D.G., Z.K., R.B., F.L.C., V.K., G.Y.O.); and Department of Physiology (Z.K., R.B., V.K., G.Y.O.), University of Alberta, Edmonton, Canada; University of Torino (F.D., E.H.), Italy; Department of Physiology (W.L., P.H.B.), University of Toronto, Canada; Beth Israel Deaconess Medical Center (S.I.), Harvard Medical School, Boston Mass; and Institute of Molecular Biotechnology of the..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilio","family":"Hirsch","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine (D.G., F.L.C., G.Y.O.); Mazankowski Alberta Heart Institute (D.G., Z.K., R.B., F.L.C., V.K., G.Y.O.); and Department of Physiology (Z.K., R.B., V.K., G.Y.O.), University of Alberta, Edmonton, Canada; University of Torino (F.D., E.H.), Italy; Department of Physiology (W.L., P.H.B.), University of Toronto, Canada; Beth Israel Deaconess Medical Center (S.I.), Harvard Medical School, Boston Mass; and Institute of Molecular Biotechnology of the..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josef M.","family":"Penninger","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine (D.G., F.L.C., G.Y.O.); Mazankowski Alberta Heart Institute (D.G., Z.K., R.B., F.L.C., V.K., G.Y.O.); and Department of Physiology (Z.K., R.B., V.K., G.Y.O.), University of Alberta, Edmonton, Canada; University of Torino (F.D., E.H.), Italy; Department of Physiology (W.L., P.H.B.), University of Toronto, Canada; Beth Israel Deaconess Medical Center (S.I.), Harvard Medical School, Boston Mass; and Institute of Molecular Biotechnology of the..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter H.","family":"Backx","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine (D.G., F.L.C., G.Y.O.); Mazankowski Alberta Heart Institute (D.G., Z.K., R.B., F.L.C., V.K., G.Y.O.); and Department of Physiology (Z.K., R.B., V.K., G.Y.O.), University of Alberta, Edmonton, Canada; University of Torino (F.D., E.H.), Italy; Department of Physiology (W.L., P.H.B.), University of Toronto, Canada; Beth Israel Deaconess Medical Center (S.I.), Harvard Medical School, Boston Mass; and Institute of Molecular Biotechnology of the..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin Y.","family":"Oudit","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine (D.G., F.L.C., G.Y.O.); Mazankowski Alberta Heart Institute (D.G., Z.K., R.B., F.L.C., V.K., G.Y.O.); and Department of Physiology (Z.K., R.B., V.K., G.Y.O.), University of Alberta, Edmonton, Canada; University of Torino (F.D., E.H.), Italy; Department of Physiology (W.L., P.H.B.), University of Toronto, Canada; Beth Israel Deaconess Medical Center (S.I.), Harvard Medical School, Boston Mass; 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