Role of Oxidation-Dependent CaMKII Activation in the Genesis of Abnormal Action Potentials in Atrial Cardiomyocytes: A Simulation Study

<div>Traces of AP, ionic currents, and calcium cycling under normal (black) and oxidative stress (red) conditions. (a) AP. (b) CaMKII activity. (c) <span class="nowrap"><svg height="11.9453pt" id="M84" style="vertical-align:-3.309401pt" version="1.1" viewbox="-0.0498162 -8.6359 20.4148 11.9453" width="20.4148pt" xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink"><g transform="matrix(.013,0,0,-0.013,0,0)"><path d="M405 650H141L135 622C222 616 230 610 215 535L133 116C118 41 113 33 29 28L23 0H289L295 28C209 33 205 40 219 116L298 535C312 609 317 616 399 622L405 650Z"></path></g><g transform="matrix(.0091,0,0,-0.0091,4.719,3.132)"><path d="M614 175C564 76 510 21 408 21C256 21 146 149 146 336C146 488 235 629 402 629C510 629 570 586 597 480L626 488C620 541 614 582 606 638C578 643 510 665 429 665C206 665 44 527 44 316C44 157 153 -15 402 -15C474 -15 558 5 586 11C604 45 629 119 643 165L614 175Z"></path></g><g transform="matrix(.0091,0,0,-0.0091,10.853,3.132)"><path d="M433 39L423 65C413 59 399 54 387 54C370 54 352 69 352 114V299C352 352 342 392 307 422C285 440 255 449 225 449C168 437 102 399 75 379C56 365 44 353 44 339C44 315 69 296 87 296C101 296 111 303 116 319C124 349 133 371 145 385C156 397 171 404 190 404C241 404 275 364 275 291V274C253 256 180 229 120 209C65 190 39 159 39 110C39 47 88 -12 159 -12C189 -12 237 25 277 52C282 35 288 21 301 8C312 -3 333 -12 348 -12L433 39ZM275 84C256 65 221 48 195 48C164 48 124 73 124 124C124 161 146 180 185 198C206 208 254 229 275 240V84Z"></path></g><g transform="matrix(.0091,0,0,-0.0091,14.848,3.132)"><path d="M495 163C480 117 462 85 444 65C421 39 387 34 332 34C290 34 256 36 236 47C218 57 213 77 213 131V526C213 612 222 616 301 622V650H40V622C122 616 128 611 128 526V126C128 41 120 34 36 28V0H489C498 31 519 126 525 157L495 163Z"></path></g></svg>.</span> (d) <span class="nowrap"><svg height="11.9453pt" id="M85" style="vertical-align:-3.309401pt" version="1.1" viewbox="-0.0498162 -8.6359 24.105 11.9453" width="24.105pt" xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink"><g transform="matrix(.013,0,0,-0.013,0,0)"><path d="M405 650H141L135 622C222 616 230 610 215 535L133 116C118 41 113 33 29 28L23 0H289L295 28C209 33 205 40 219 116L298 535C312 609 317 616 399 622L405 650Z"></path></g><g transform="matrix(.0091,0,0,-0.0091,4.719,3.132)"><path d="M719 650H483V622C553 619 576 606 581 560C585 532 588 487 588 394V148H585L167 650H20V622C67 618 88 610 109 585C127 562 129 557 129 484V264C129 173 126 124 123 93C118 44 92 31 35 28V0H272V28C204 32 181 44 176 95C173 124 170 172 170 264V515H172L598 -9H629V394C629 487 631 532 635 563C639 606 663 619 719 622V650Z"></path></g><g transform="matrix(.0091,0,0,-0.0091,11.416,3.132)"><path d="M614 175C564 76 510 21 408 21C256 21 146 149 146 336C146 488 235 629 402 629C510 629 570 586 597 480L626 488C620 541 614 582 606 638C578 643 510 665 429 665C206 665 44 527 44 316C44 157 153 -15 402 -15C474 -15 558 5 586 11C604 45 629 119 643 165L614 175Z"></path></g><g transform="matrix(.0091,0,0,-0.0091,17.468,3.132)"><path d="M655 0V28C585 35 563 50 517 120C469 193 414 280 360 366C427 469 460 516 481 545C526 604 545 614 619 622V650H391V622C457 614 462 604 438 560C411 511 381 463 339 398C295 466 258 523 225 580C210 606 211 615 272 622V650H26V622C98 614 111 603 154 538C189 482 235 408 288 324C200 188 149 116 124 85C95 47 64 34 7 28V0H236V28C169 36 164 46 188 89C220 148 261 217 310 291C372 193 417 118 442 77C461 44 454 35 392 28V0H655Z"></path></g></svg>.</span> (e) Fraction of RyR phosphorylation. (f) Fraction of PLB phosphorylation. (g) <span class="nowrap"><svg height="11.9087pt" id="M86" style="vertical-align:-3.2728pt" version="1.1" viewbox="-0.0498162 -8.6359 15.074 11.9087" width="15.074pt" xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink"><g transform="matrix(.013,0,0,-0.013,0,0)"><path d="M429 650H175L169 622C251 614 259 612 244 532L174 152C163 91 152 37 135 -6C109 -72 67 -101 23 -113L33 -144C45 -143 73 -134 102 -119C186 -76 229 -1 254 133L327 532C341 609 347 613 423 622L429 650Z"></path></g><g transform="matrix(.0091,0,0,-0.0091,5.031,3.132)"><path d="M181 342V451C133 431 89 419 40 411V388C98 381 102 377 102 311V104C102 38 95 32 33 26V0H263V26C186 32 181 38 181 104V287C203 343 235 372 261 372C277 372 289 366 304 352C310 346 318 345 330 350C349 359 362 379 362 399C362 422 338 449 304 449C256 449 213 393 183 342H181Z"></path></g><g transform="matrix(.0091,0,0,-0.0091,8.288,3.132)"><path d="M380 106C343 72 306 56 265 56C195 56 116 112 115 248C235 252 361 262 377 265C396 269 400 277 400 297C400 374 333 449 250 449H249C198 449 144 421 103 376S37 269 37 201C37 88 109 -12 232 -12C263 -12 332 6 395 84L380 106ZM225 412C281 412 315 364 314 312C314 297 308 292 290 292C232 290 176 289 120 289C135 370 180 412 225 412Z"></path></g><g transform="matrix(.0091,0,0,-0.0091,12.119,3.132)"><path d="M238 0V26C174 32 166 38 166 104V712C132 700 70 683 18 677V653C81 647 87 645 87 577V104C87 38 78 32 15 26V0H238Z"></path></g></svg>.</span> (h) <span class="nowrap"><svg height="14.0004pt" id="M87" style="vertical-align:-5.3645pt" version="1.1" viewbox="-0.0498162 -8.6359 15.1745 14.0004" width="15.1745pt" xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink"><g transform="matrix(.013,0,0,-0.013,0,0)"><path d="M429 650H175L169 622C251 614 259 612 244 532L174 152C163 91 152 37 135 -6C109 -72 67 -101 23 -113L33 -144C45 -143 73 -134 102 -119C186 -76 229 -1 254 133L327 532C341 609 347 613 423 622L429 650Z"></path></g><g transform="matrix(.0091,0,0,-0.0091,5.031,3.132)"><path d="M518 50L491 51C452 54 444 60 444 110V444C429 441 405 437 377 434C348 430 314 427 287 426V403L323 397C356 392 365 386 365 333V99C331 66 293 51 257 51C212 51 169 75 169 164V299C169 366 169 413 172 444C156 441 128 437 101 433C75 430 50 427 29 426V403L57 397C82 391 90 386 90 333V137C90 29 147 -12 214 -12C241 -12 262 -4 291 13S342 48 365 65V-6L371 -12C390 -7 415 1 441 8C468 15 496 21 518 24V50Z"></path></g><g transform="matrix(.0091,0,0,-0.0091,9.753,3.132)"><path d="M169 380V459C122 440 66 423 24 416V392C86 384 90 382 90 317V-135C90 -201 81 -207 17 -213V-240H253V-213C176 -207 169 -201 169 -125V6C182 -1 208 -11 238 -12C368 12 487 109 487 260C487 358 421 449 310 449C298 449 279 444 261 433L169 380ZM169 346C196 367 237 389 269 389C341 389 403 329 403 221C403 109 347 37 263 37C228 37 191 53 169 76V346Z"></path></g></svg>.</span> (i) <span class="nowrap"><svg height="11.9087pt" id="M88" style="vertical-align:-3.2728pt" version="1.1" viewbox="-0.0498162 -8.6359 20.4814 11.9087" width="20.4814pt" xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink"><g transform="matrix(.013,0,0,-0.013,0,0)"><path d="M429 650H175L169 622C251 614 259 612 244 532L174 152C163 91 152 37 135 -6C109 -72 67 -101 23 -113L33 -144C45 -143 73 -134 102 -119C186 -76 229 -1 254 133L327 532C341 609 347 613 423 622L429 650Z"></path></g><g transform="matrix(.0091,0,0,-0.0091,5.031,3.132)"><path d="M238 0V26C174 32 166 38 166 104V712C132 700 70 683 18 677V653C81 647 87 645 87 577V104C87 38 78 32 15 26V0H238Z"></path></g><g transform="matrix(.0091,0,0,-0.0091,7.333,3.132)"><path d="M380 106C343 72 306 56 265 56C195 56 116 112 115 248C235 252 361 262 377 265C396 269 400 277 400 297C400 374 333 449 250 449H249C198 449 144 421 103 376S37 269 37 201C37 88 109 -12 232 -12C263 -12 332 6 395 84L380 106ZM225 412C281 412 315 364 314 312C314 297 308 292 290 292C232 290 176 289 120 289C135 370 180 412 225 412Z"></path></g><g transform="matrix(.0091,0,0,-0.0091,11.256,3.132)"><path d="M433 39L423 65C413 59 399 54 387 54C370 54 352 69 352 114V299C352 352 342 392 307 422C285 440 255 449 225 449C168 437 102 399 75 379C56 365 44 353 44 339C44 315 69 296 87 296C101 296 111 303 116 319C124 349 133 371 145 385C156 397 171 404 190 404C241 404 275 364 275 291V274C253 256 180 229 120 209C65 190 39 159 39 110C39 47 88 -12 159 -12C189 -12 237 25 277 52C282 35 288 21 301 8C312 -3 333 -12 348 -12L433 39ZM275 84C256 65 221 48 195 48C164 48 124 73 124 124C124 161 146 180 185 198C206 208 254 229 275 240V84Z"></path></g><g transform="matrix(.0091,0,0,-0.0091,15.296,3.132)"><path d="M513 0V26C475 28 448 43 413 81C379 116 277 234 258 264C301 314 319 334 344 359C383 396 404 407 473 418V443L269 434V408C317 403 320 395 299 364C280 337 250 298 228 276C213 260 195 247 165 241V712C126 699 69 682 21 677V653C82 648 87 642 87 576V104C87 40 81 32 14 26V0H237V26C173 32 165 38 165 104V215C171 217 176 218 181 218C189 218 198 212 212 196C267 129 330 49 376 -2L513 0Z"></path></g></svg>.</span> (j) <span class="nowrap"><svg height="14.8825pt" id="M89" style="vertical-align:-3.2911pt" version="1.1" viewbox="-0.0498162 -11.5914 37.0921 14.8825" width="37.0921pt" xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink"><g transform="matrix(.013,0,0,-0.013,0,0)"><path d="M290 -163V-135C183 -126 181 -122 181 -44V583C181 662 184 666 290 675V703H120V-163H290Z"></path></g><g transform="matrix(.013,0,0,-0.013,4.485,0)"><path d="M614 175C564 76 510 21 408 21C256 21 146 149 146 336C146 488 235 629 402 629C510 629 570 586 597 480L626 488C620 541 614 582 606 638C578 643 510 665 429 665C206 665 44 527 44 316C44 157 153 -15 402 -15C474 -15 558 5 586 11C604 45 629 119 643 165L614 175Z"></path></g><g transform="matrix(.013,0,0,-0.013,13.162,0)"><path d="M433 39L423 65C413 59 399 54 387 54C370 54 352 69 352 114V299C352 352 342 392 307 422C285 440 255 449 225 449C168 437 102 399 75 379C56 365 44 353 44 339C44 315 69 296 87 296C101 296 111 303 116 319C124 349 133 371 145 385C156 397 171 404 190 404C241 404 275 364 275 291V274C253 256 180 229 120 209C65 190 39 159 39 110C39 47 88 -12 159 -12C189 -12 237 25 277 52C282 35 288 21 301 8C312 -3 333 -12 348 -12L433 39ZM275 84C256 65 221 48 195 48C164 48 124 73 124 124C124 161 146 180 185 198C206 208 254 229 275 240V84Z"></path></g><g transform="matrix(.0091,0,0,-0.0091,18.891,-5.741)"><path d="M414 144C384 79 371 75 317 75H135L276 221C367 316 408 376 408 465C408 570 327 635 237 635C179 635 131 609 100 575L42 494L67 471C94 510 138 565 205 565C277 565 321 517 321 435C321 348 258 270 195 195C146 137 88 81 33 26V0H411C423 44 433 88 446 135L414 144Z"></path></g><g transform="matrix(.0091,0,0,-0.0091,23.322,-5.741)"><path d="M556 236V289H337V504H275V289H56V236H275V-4H337V236H556Z"></path></g><g transform="matrix(.013,0,0,-0.013,29.418,0)"><path d="M226 -163V703H56V676C162 667 165 662 165 584V-43C165 -122 162 -126 56 -136V-163H226Z"></path></g><g transform="matrix(.0091,0,0,-0.0091,33.903,3.132)"><path d="M250 606C250 634 233 656 203 656C168 656 146 618 146 593C146 564 169 545 192 545C227 545 250 573 250 606ZM227 95L212 119C187 98 152 71 135 71C129 71 128 78 134 102L207 373C219 418 217 451 194 451C165 451 92 411 30 351L44 326C77 353 106 371 114 371C124 371 121 357 117 341L55 97C32 5 46 -12 70 -12C108 -12 191 51 227 95Z"></path></g></svg>.</span> (k) [Ca<sup>2+</sup>]<sub>SR</sub>. (l) Intracellular Na<sup>+</sup> concentration (<span class="nowrap"><svg height="14.0878pt" id="M90" style="vertical-align:-3.291101pt" version="1.1" viewbox="-0.0498162 -10.7967 33.6616 14.0878" width="33.6616pt" xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink"><g transform="matrix(.013,0,0,-0.013,0,0)"><path d="M290 -163V-135C183 -126 181 -122 181 -44V583C181 662 184 666 290 675V703H120V-163H290Z"></path></g><g transform="matrix(.013,0,0,-0.013,4.485,0)"><path d="M719 650H483V622C553 619 576 606 581 560C585 532 588 487 588 394V148H585L167 650H20V622C67 618 88 610 109 585C127 562 129 557 129 484V264C129 173 126 124 123 93C118 44 92 31 35 28V0H272V28C204 32 181 44 176 95C173 124 170 172 170 264V515H172L598 -9H629V394C629 487 631 532 635 563C639 606 663 619 719 622V650Z"></path></g><g transform="matrix(.013,0,0,-0.013,14.18,0)"><path d="M433 39L423 65C413 59 399 54 387 54C370 54 352 69 352 114V299C352 352 342 392 307 422C285 440 255 449 225 449C168 437 102 399 75 379C56 365 44 353 44 339C44 315 69 296 87 296C101 296 111 303 116 319C124 349 133 371 145 385C156 397 171 404 190 404C241 404 275 364 275 291V274C253 256 180 229 120 209C65 190 39 159 39 110C39 47 88 -12 159 -12C189 -12 237 25 277 52C282 35 288 21 301 8C312 -3 333 -12 348 -12L433 39ZM275 84C256 65 221 48 195 48C164 48 124 73 124 124C124 161 146 180 185 198C206 208 254 229 275 240V84Z"></path></g><g transform="matrix(.0091,0,0,-0.0091,19.909,-5.741)"><path d="M556 236V289H337V504H275V289H56V236H275V-4H337V236H556Z"></path></g><g transform="matrix(.013,0,0,-0.013,25.988,0)"><path d="M226 -163V703H56V676C162 667 165 662 165 584V-43C165 -122 162 -126 56 -136V-163H226Z"></path></g><g transform="matrix(.0091,0,0,-0.0091,30.473,3.132)"><path d="M250 606C250 634 233 656 203 656C168 656 146 618 146 593C146 564 169 545 192 545C227 545 250 573 250 606ZM227 95L212 119C187 98 152 71 135 71C129 71 128 78 134 102L207 373C219 418 217 451 194 451C165 451 92 411 30 351L44 326C77 353 106 371 114 371C124 371 121 357 117 341L55 97C32 5 46 -12 70 -12C108 -12 191 51 227 95Z"></path></g></svg>).</span></div>

BioMed Research International

fig5

Figure 5

Figure 5: Role of Oxidation-Dependent CaMKII Activation in the Genesis of Abnormal Action Potentials in Atrial Cardiomyocytes: A Simulation Study 