Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist

Abstract

<p id="d8669151e432">A significant factor influencing longevity and quality of life in heart attack survivors is the extent of adverse tissue remodeling in injured heart tissue, which impedes mechanical function and accelerates the progression of heart failure. Despite the general consensus that mitigating fibrotic responses would delay the onset of heart failure and improve heart function after a heart attack, there currently are no agents that directly target this pathological process available for heart disease management. Here we demonstrate that chemical inhibition of the Wnt acyltransferase Porcupine results in improvements in heart function following myocardial infarction in mice. Our findings advocate for the development of Porcupine inhibitors as proregenerative agents in the heart and other tissues. </p><p class="first" id="d8669151e435">The secreted Wnt signaling molecules are essential to the coordination of cell-fate decision making in multicellular organisms. In adult animals, the secreted Wnt proteins are critical for tissue regeneration and frequently contribute to cancer. Small molecules that disable the Wnt acyltransferase Porcupine (Porcn) are candidate anticancer agents in clinical testing. Here we have systematically assessed the effects of the Porcn inhibitor (WNT-974) on the regeneration of several tissue types to identify potentially unwanted chemical effects that could limit the therapeutic utility of such agents. An unanticipated observation from these studies is proregenerative responses in heart muscle induced by systemic chemical suppression of Wnt signaling. Using in vitro cultures of several cell types found in the heart, we delineate the Wnt signaling apparatus supporting an antiregenerative transcriptional program that includes a subunit of the nonfibrillar collagen VI. Similar to observations seen in animals exposed to WNT-974, deletion of the collagen VI subunit, <i>COL6A1</i>, has been shown to decrease aberrant remodeling and fibrosis in infarcted heart tissue. We demonstrate that WNT-974 can improve the recovery of heart function after left anterior descending coronary artery ligation by mitigating adverse remodeling of infarcted tissue. Injured heart tissue exposed to WNT-974 exhibits decreased scarring and reduced Col6 production. Our findings support the development of Porcn inhibitors as antifibrotic agents that could be exploited to promote heart repair following injury. </p>