New tar­get for treat­ing heart fail­ure iden­ti­fied

Iran Daily - - Health -

Changes in cel­lu­lar struts called mi­cro­tubules (MT) can af­fect the stiff­ness of dis­eased hu­man heart mus­cle cells, and re­vers­ing these mod­i­fi­ca­tions can lessen the stiff­ness and im­prove the beat­ing strength of these cells iso­lated from trans­plant pa­tients with heart fail­ure, found re­searchers from the Perel­man School of Medicine at the Univer­sity of Penn­syl­va­nia.

This Na­ture Medicine new study is a con­tin­u­a­tion of re­search con­ducted two years ago on how MTS are in­volved in reg­u­lat­ing the heart­beat, med­i­calx­ re­ported.

Se­nior au­thor Ben Prosser, PHD, an as­sis­tant pro­fes­sor of phys­i­ol­ogy, said, “These find­ings pro­vide com­pelling ev­i­dence from hu­man sam­ples for a new ther­a­peu­tic tar­get for heart dis­ease.”

The Penn­syl­va­nia in­ves­ti­ga­tors aim to de­velop ther­a­pies that seek out the dam­aged MTS to re­verse their harm­ful in­flu­ence.

By sup­press­ing im­paired MTS, the team im­proved heart mus­cle cell func­tion in dam­aged hu­man cells. Nor­mally, MTS of the cell’s in­ner sup­port sys­tem have di­verse struc­tural and sig­nal­ing roles.

Al­ter­ations in this net­work have been sug­gested to con­trib­ute to heart dis­ease. Re­cent stud­ies sug­gest that chem­i­cal changes to the MTS, called de­ty­rosi­na­tion (the re­moval of a ty­ro­sine chem­i­cal group), con­trol the me­chan­ics of heart beats. De­ty­rosi­nated MTS pro­vide re­sis­tance that can im­pede the mo­tion of con­tract­ing heart mus­cle cells.

The Penn­syl­va­nia team used mass spec­trom­e­try and me­chan­i­cal tests of sin­gle heart mus­cle cells to char­ac­ter­ize changes to the MT net­work and its con­se­quences for nor­mal heart func­tion.

Anal­y­sis of tis­sue from the left ven­tri­cle of heart trans­plant pa­tients re­vealed a con­sis­tent up­reg­u­la­tion of pro­teins that leads to the stiff­en­ing of MTS. Us­ing su­per-res­o­lu­tion imag­ing, the team also saw a dense, heav­ily de­ty­rosi­nated MT net­work in the dis­eased heart mus­cle cells, which is con­sis­tent with in­creased cell stiff­ness and de­creased abil­ity to contract. Proper cell elas­tic­ity and con­trac­tion is cru­cial for nor­mal cir­cu­la­tion through­out the body.

Us­ing a drug, the team sup­pressed the de­ty­rosi­nated MTS, which re­stored about half of lost con­trac­tile func­tion in the dis­eased cells. Ge­net­i­cally re­duc­ing the MT de­ty­rosi­na­tion also soft­ened the dis­eased cells and im­proved their abil­ity to contract.

Past clin­i­cal data from Penn showed a direct cor­re­la­tion be­tween ex­cess MT de­ty­rosi­na­tion and a de­cline in heart func­tion among pa­tients with hy­per­trophic car­diomy­opa­thy, a con­di­tion in which thick­ened heart mus­cle can cause prob­lems in main­tain­ing proper blood pres­sure lev­els and flow of blood through the heart. The team found that de­ty­rosi­na­tion was greater in dis­eased hearts by com­par­ing hu­man heart tis­sue do­nated from heart trans­plant pa­tients to nor­mal heart tis­sue from other donors, ob­tained from work with trans­plant car­di­ol­o­gist and coau­thor Ken Mar­gulies, MD, a pro­fes­sor of car­dio­vas­cu­lar medicine. Cells from dis­eased hearts have more MTS, and these MTS have more de­ty­rosi­na­tion.

This process cor­re­lated with im­paired func­tion within this pa­tient pop­u­la­tion in that their whole hearts, be­fore the trans­plant, had a lower ejec­tion frac­tion that cor­re­lated with greater de­ty­rosi­na­tion. Ejec­tion frac­tion, an in­di­ca­tor of heart health, mea­sures the amount of blood pumped out of ven­tri­cles with each con­trac­tion.

The team is now work­ing on ways to tar­get only heart mus­cle cell MTS. They are re­fin­ing gene ther­apy ap­proaches with the Penn Gene Vec­tor Core to de­liver an en­zyme to the heart that re­verses de­ty­rosi­na­tion in heart mus­cle cells.


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