Neutral Sphingomyelinase Regulates Mechano-Transduction in Human Engineered Cardiac Tissues and Mouse Hearts

Details

• Alternative Title:
  J Physiol
• Personal Author:
  Turner, Daniel G. P. ; De Lange, Willem J. ; Zhu, Yanlong ; Coe, Christopher L. ; Simcox, Judith ; Ge, Ying ; Kamp, Timothy J. ; Ralphe, J. Carter ; Glukhov, Alexey V.
• Description:
  Cardiovascular disease is the leading cause of death in the USA and is known to be exacerbated by elevated mechanical stress from hypertension. 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)-derived cardiomyocytes and hiPSC-derived cardiac fibroblasts, to develop a long-term cyclic stretch protocol that recapitulates the effects of hypertension on caveolae expression, membrane tension, and the β-adrenergic response. Leveraging this new stretch protocol, we identified neutral sphingomyelinases (nSMase) as mechanoregulated mediators of caveolae loss, ceramide production and the blunted β-adrenergic response in this human cardiac model. Specifically, in our ECT model, nSMase inhibition via GW4869 prevented stretch-induced loss of caveolae-like structures, mitigated nSMase-dependent ceramide production, and maintained the ECT contractile kinetic response to isoprenaline. These findings are correlated with a blood lipidomic analysis in middle-aged 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-induced effects on cardiac function. KEY POINTS: 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. Stretch of engineered cardiac tissue induces activation of neutral sphingomyelinase (nSMase), generation of ceramide, and disassembly of caveolae. Activation of nSMase blunts cardiac β-adrenergic contractile kinetics and mediates stretch-induced slowing of conduction and upstroke velocity. Circulating ceramides are increased in adults with hypertension, highlighting the clinical relevance of stretch-induced nSMase activity.
• Subjects:
  Aniline Compounds Animals Benzylidene Compounds Caveolae Ceramides Humans Induced Pluripotent Stem Cells Isoproterenol Male Mechanotransduction, Cellular Mice Middle Aged Myocardium Myocytes, Cardiac Sphingomyelin Phosphodiesterase Tissue Engineering

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• Keywords:
  Alzheimer's Disease Alzheimer's Disease Sequencing Project Antiviral Agents Ceramide Herpes Simplex Human Papillomavirus Hypertension Neutral Sphingomyelinase Stretch Tissue Engineering Torque Teno Viruses Whole Exome Sequencing Whole Genome Sequencing

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• Source:
  J Physiol. 602(18):4387-4407
• Pubmed ID:
  37889115
• Pubmed Central ID:
  PMC11052922
• Document Type:
  Journal Article
• Funding:
  R01HL139738/HL/NHLBI NIH HHSUnited States/ ; R01 HL139738/HL/NHLBI NIH HHSUnited States/ ; U01 AG077928/AG/NIA NIH HHSUnited States/ ; S10 OD018475/CD/ODCDC CDC HHSUnited States/ ; P30 CA014520/CA/NCI NIH HHSUnited States/ ; GM117058/GM/NIGMS NIH HHSUnited States/ ; U19AG051426/AG/NIA NIH HHSUnited States/ ; GM125085/GM/NIGMS NIH HHSUnited States/ ; R01 GM125085/GM/NIGMS NIH HHSUnited States/ ; U19 AG051426/AG/NIA NIH HHSUnited States/ ; S10 OD018475/OD/NIH HHSUnited States/ ; R01HL146652/HL/NHLBI NIH HHSUnited States/ ; R01 HL141214/HL/NHLBI NIH HHSUnited States/ ; R21 AG030166/AG/NIA NIH HHSUnited States/ ; T32 GM008688/GM/NIGMS NIH HHSUnited States/ ; P01AG030166/AG/NIA NIH HHSUnited States/ ; R01 GM117058/GM/NIGMS NIH HHSUnited States/ ; R01HL096971/HL/NHLBI NIH HHSUnited States/ ; S10 OD023526/OD/NIH HHSUnited States/ ; R01 HL096971/HL/NHLBI NIH HHSUnited States/ ; R01 HL146652/HL/NHLBI NIH HHSUnited States/ ; T32GM008688/GM/NIGMS NIH HHSUnited States/ ; R01HL141214/HL/NHLBI NIH HHSUnited States/ ; P01 AG020166/AG/NIA NIH HHSUnited States/ ; R01HL141214/HL/NHLBI NIH HHSUnited States/ ; R01HL139738/HL/NHLBI NIH HHSUnited States/ ; R01HL146652/HL/NHLBI NIH HHSUnited States/ ; R01HL096971/HL/NHLBI NIH HHSUnited States/ ; 16SDG29120011/American Heart Association/ ; 903203/American Heart Association/ ; T32GM008688/GM/NIGMS NIH HHSUnited States/ ; GM125085/GM/NIGMS NIH HHSUnited States/ ; GM117058/GM/NIGMS NIH HHSUnited States/ ; 4140/Wisconsin Partnership Program/ ; S10 OD018475/CD/ODCDC CDC HHSUnited States/ ; P01AG030166/AG/NIA NIH HHSUnited States/ ; U19AG051426/AG/NIA NIH HHSUnited States/
• Volume:
  602
• Issue:
  18
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha-512:8e6f396572beedd2eccedaf59f3a1a6ff9b67454e08467381bbd7d760e50e916f2ae279d74e81a26d3f20fc5a2dafeba0f625ea1bbd530ad7210ee654d4d3a02
• Download URL:
  https://stacks.cdc.gov/view/cdc/154847/cdc_154847_DS1.pdf
• File Type:
  [PDF - 3.08 MB ]