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AAV-mediated knock-down of HRC exacerbates transverse aorta constriction-induced heart failure

Chang Sik Park1, Hyeseon Cha, Eun Jeong Kwon

  • 1College of Life Sciences and Systems Biology Research Center, Gwangju Institute of Science and Technology (GIST), Buk-gu, Gwangju, Republic of Korea.

Plos One
|September 7, 2012
PubMed

Insights

Histidine-rich calcium binding protein (HRC) knockdown worsened cardiac function in heart failure models. Downregulating HRC disrupted calcium cycling, leading to increased cell death and fibrosis, contrary to initial expectations.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Biochemistry

Background:

  • Histidine-rich calcium binding protein (HRC) is crucial for sarcoplasmic reticulum (SR) Ca(2+) handling, interacting with triadin and SERCA.
  • Altered HRC levels are implicated in cardiac hypertrophy and dysfunction.
  • Previous studies suggested HRC modulation affects Ca(2+) cycling, but its role in established heart failure was unclear.

Purpose of the Study:

  • To investigate the functional role of HRC in cardiac Ca(2+) cycling and its impact on cardiac hypertrophy.
  • To characterize the effects of HRC knockdown (KD) in a mouse model of transverse aortic constriction-induced heart failure (TAC-FH).

Main Methods:

  • In vitro siRNA-mediated HRC KD in neonatal rat ventricular cells and HL-1 cells.
  • In vivo adeno-associated virus (AAV)-mediated HRC KD in a C57BL/6 mouse model of TAC-induced failing heart (TAC-FH).
  • Assessment of cardiac function, fibrosis, SR Ca(2+) cycling, and key signaling pathways (RyR2, CaMKII, MAPK).

Main Results:

  • In vitro HRC KD enhanced Ca(2+) cycling and RyR2/SERCA2 activity without altering SR Ca(2+) load.
  • In vivo AAV9-mediated HRC KD in TAC-FH mice led to decreased fractional shortening and increased cardiac fibrosis.
  • HRC KD in TAC-FH mice upregulated phospho-RyR2, phospho-CaMKII, phospho-p38 MAPK, and phospho-PLB, alongside increased cleaved caspase-3 and positive TUNEL assay results.

Conclusions:

  • Partial HRC knockdown increases Ca(2+) leak and cytosolic Ca(2+) concentration.
  • This perturbation activates CaMKII and p38 MAPK pathways, initiating mitochondrial cell death.
  • Downregulation of HRC exacerbates cardiac dysfunction in TAC-FH by disrupting SR-mediated Ca(2+) cycling.
Abstract

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