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Caveolae are plasma membrane structures that buffer mechanical stress but have been found to be reduced in pathological conditions associated with chronically stretched myocardium. To explore the physiological implications of the loss of caveolae, we used human engineered cardiac tissue (ECT) constructs, composed of human induced pluripotent stem cell (hiPSC)\u2010derived cardiomyocytes and hiPSC\u2010derived cardiac fibroblasts, to develop a long\u2010term cyclic stretch protocol that recapitulates the effects of hypertension on caveolae expression, membrane tension, and the \u03b2\u2010adrenergic response. Leveraging this new stretch protocol, we identified neutral sphingomyelinases (nSMase) as mechanoregulated mediators of caveolae loss, ceramide production and the blunted \u03b2\u2010adrenergic response in this human cardiac model. Specifically, in our ECT model, nSMase inhibition via GW4869 prevented stretch\u2010induced loss of caveolae\u2010like structures, mitigated nSMase\u2010dependent ceramide production, and maintained the ECT contractile kinetic response to isoprenaline. These findings are correlated with a blood lipidomic analysis in middle\u2010aged and older adults, which revealed an increase of the circulating levels of ceramides in adults with hypertension. Furthermore, we found that conduction slowing from increased pressure loading in mouse left ventricle was abolished in the context of nSMase inhibition. Collectively, these findings identify nSMase as a potent drug target for mitigating stretch\u2010induced effects on cardiac function.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15789-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>We have developed a new stretch protocol for human engineered cardiac tissue that recapitulates changes in plasma membrane morphology observed in animal models of pressure\/volume overload.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Stretch of engineered cardiac tissue induces activation of neutral sphingomyelinase (nSMase), generation of ceramide, and disassembly of caveolae.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Activation of nSMase blunts cardiac \u03b2\u2010adrenergic contractile kinetics and mediates stretch\u2010induced slowing of conduction and upstroke velocity.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Circulating ceramides are increased in adults with hypertension, highlighting the clinical relevance of stretch\u2010induced nSMase activity.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp284807","type":"journal-article","created":{"date-parts":[[2023,10,27]],"date-time":"2023-10-27T13:41:49Z","timestamp":1698414109000},"page":"4387-4407","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Neutral sphingomyelinase regulates mechanotransduction in human engineered cardiac tissues and mouse hearts"],"prefix":"10.1113","volume":"602","author":[{"given":"Daniel G. 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