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	Figure 1. A‐B, longitudinal (A) and transverse (B) section of the normal/healthy heart. C‐D, longitudinal (C) and transverse (D) section of the remodeled heart. A, atrium; LV, left ventricle; RV; right ventricle.
	Figure 2. Molecular pathway of cardiac remodeling.
	Figure 3. β1 and β2 AR coupling and signal transduction in cardiac myocytes. β2 AR acts on cell survival signals through Gs‐cAMP‐PKA‐Akt and Gi‐PI3K‐AktGβγ pathways. In contrast, β1 AR binds to Gs, which activates PKA‐independent, CamKII‐mediated apoptotic pathway. ECC, excitation‐contraction coupling.
	Figure 4. G‐protein‐mediated signal transduction. Agonist binds to the receptor, which leads to the exchange of G‐protein‐bound GDP for GTP. Gα and Gβγ subunits are dissociated from the activated form of G‐protein. Gα is classified into four subclasses, including Gαs, Gαi, Gαq, and Gα12. Gαs is a stimulatory member, which binds to adenylyl cyclase (AC) and increases intracellular cAMP levels. Gαi is an inhibitory member which decreases cAMP levels. Gαq activates PLC‐β, whereas Gα12 acts on Rac and Rho. Gβγ dimers activate ion channels, MAP (mitogen‐activated protein) kinase and activate or inhibit AC.
	Figure 5. Adrenergic receptors in human cardiac tissue. These receptors bind to the two effector pathways in human myocyte. AC, adenylyl cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; DG, diacylglycerol; GDP, guanine diphosphate; GTP, guanosine triphosphate; IP3, inositol triphosphate; PIP2, phosphatidylinositol 4,5‐bisphosphate; PLC, phospholipase C.
	Figure 6. Mechanisms of pathological changes caused by ROS in the heart. ROS induces three different pathways, including PKC and PKB, MAPK, and TNFα.
	Figure 7. Phases of myocardial wound healing post‐MI in patients. Depicted are the four phases of myocardial wound healing that occur following a myocardial infarction (MI). Note the overlapping time courses between inflammation, formation of granulation tissue, and scar formation phases.
	Figure 8. TGFβ1/Smad‐independent signaling: p38 MAPK. In addition to its role in stimulating a Smad‐dependent pathway, extracellular TGFβ1 can stimulate a Smad‐independent pathway through TβRs. TGFβ1 promotes ubiquitination of TRAF6 (B), which in turn phosphorylates and forms a complex with TAK1. This activated complex induces phosphorylation of MKK3/6, which activates p38 kinase through phosphorylation. Activated p38 then has the capability to phosphorylate downstream transcription factors such as ATF2, CHOP, and CREB or the linker region of R‐Smad proteins to regulate their function. TGFβ1 also promotes phosphorylation of PI3K (C), which in turn phosphorylates Akt and PAK2. Signaling through the Akt pathway leads to cell migration, whereas signaling through a PAK2 dependent pathway leads to morphological transformation and cell proliferation. Actin organization, stabilization, and stress fiber formation are potently regulated by TGFβ1 signaling through a Smad‐independent pathway. Activation of TβRI promotes the activation of RhoA (D). RhoA can then induce the activity of both mDia and ROCK by phosphorylation. ROCK activation leads to phosphorylation of MRTF and the formation of a complex with SRF. Additionally, ROCK stimulates LIMK, which represses cofilin. Collectively, these pathways lead to actin cytoskeleton organization, F‐actin stabilization, and stress fiber formation. In addition, ERK1/2 (A) is a well‐described TGFβ1 triggered signal pathway that is Smad independent. TGFβ1 stimulation of its receptors leads to the phosphorylation of the adaptor protein Shc. Active Shc forms a complex with Grb2 and SOS, which is capable of promoting activation of Ras. Activation of Ras leads to a MAPK signaling cascade, which ultimately leads to phosphorylation of ERK1/2 through MEK1/2. Erk1/2 can then phosphorylate transcription factors, such as Elk1, to modify gene expression.
	Figure 9. Protein structure of Ski. The human Ski protein is depicted earlier. At the NH2 end of the protein lies a DHD, that plays a critical role in protein‐protein interactions, and an R‐Smad2/3 interacting domain that is important for Ski's ability to repress TGFβ/Smad‐dependent signaling. Slightly further downstream lies the unique C2H2 (SAND) domain that regulates the interaction of Ski with Co‐Smad4. The COOH end of the protein is less conserved than that of the NH2 end. However, the COOH terminal plays an important role in Ski:Sno homo‐ and hetero‐dimerization as well as nuclear translocation of Ski [PRKRKLT—nuclear localization signal (NLS)].
	Figure 10. Ski‐mediated repression of TGFβ1/Smad signaling. (A) Ski is primarily a nuclear protein. Within the nucleus, Ski can inhibit Smad dependent signaling by forming an inhibitory complex with the R‐Smad/Co‐Smad complex and stabilize them while bound to DNA. Ski then recruits a transcriptional inhibitory complex that includes NCoR, mSin3a, and HDACs to inhibit gene transcription. Ski can also be found within the cytoplasmic fraction of cells. Although its function has been extensively described in the nucleus, Ski can repress TGFβ1/Smad signaling from the cytoplasm in two ways. First, (B) Ski can form a complex with the Smad complex and prevent nuclear translocation. Second, (C) Ski can prevent R‐Smad phosphorylation at the level of the TβRI and prevent R‐Smad complex formation at the initiating step.
	Figure 11. Schematic of the reciprocal hypothesis. Ski and Scx form a negative feedback loop that regulates their gene expression. In the chronic post‐MI setting, we believe that this balance is tipped in favor of Scx, which promotes repression of Ski transcription leading to remodeling of the cardiac matrix. With TGFβ1 signaling unchecked by Ski, there is a significant increase in expression of fibrillar collagens and matrix proteins that ultimately cumulate to interstitial fibrosis and HF.
	Figure 12. Proposed mechanism for the regulation of Scx by p44/42 (ERK1/2) and Ski. TGFβ1 is a powerful inducer of Scx expression. We have demonstrated that TGFβ1 may exert its effects on Scx expression through a TGFβ1/Smad‐independent mechanism that includes the p44/42 MAPK signaling pathway in combination with c‐Jun activation in cardiac myofibroblasts. As we did not completely restore abrogated Scx protein expression with the MEK1/2 inhibitor U0126, Smad proteins may still be involved in regulating Scx through an alternative mechanism that has yet to be described. We have shown Ski to be a potent inhibitor of Scx signaling and we propose that Ski exerts its effects through inhibition of p44/42 in addition to its role in preventing Smad‐mediated gene regulation.
	Figure 13. Application of naturally derived and synthetic biomaterials in cardiovascular tissue engineering. (A) Representative images from highly elastic scaffold made from the methacrylate form of tropoelastin (MeTro) before and after stretching. Extensible MeTro molecule with an asymmetric coil and a C‐terminal cell interactive motif. (B) Images of MeTro‐based hydrogels under torsion test before (left) and after 27 rotations (right). (C) No breakage in the hydrogel structure was observed after twisting. Reprinted with permission from (18). Copyright 2015, WILEY‐VCH Verlag GmbH & Co. (D) Fluorescent images of cardiac fibroblasts cultured on random and aligned electrospun scaffolds made from gelatin:PGS blend. Cells were stained for α‐SMA (red), F‐actin (green), and DAPI (blue) after 5 days of culture. Reprinted with permission from (258). Copyright 2013, Elsevier.

Teaching Material

Didactic Synopsis

Major Teaching Points:

Major teaching points of the current review include: (1) learning functional anatomy of the heart, which describe fundamental structural unit of the organ and its importance in understanding of HF concepts. (ii) Understanding role of RAAS (Renin-Angiotensin-Aldosterone System) in HF via regulation of the homeostasis of arterial pressure, fluid volume, heart perfusion, extracellular volume, the vascular response to injury, and inflammation. (iii) Getting deep knowledge on the role of adrenergic receptor signaling pathway in HF. (iv) Justifying how ROS is involved in HF signaling pathway. (v) Understanding the role of heart fibroblast and myofibroblast in heart fibrosis focusing on the importance of TGF-β1 canonical and noncanonical signaling in heart fibrosis and pathogenesis of heart HF. (vi) Potential therapeutic targets in HF including anti-inflammation therapy, antioxidant therapy and stem cell therapy (vii) Being familiar with concept of cardiac tissue engineering and repair in modern regenerative medicine.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching points: Structural analysis of the heart to understand longitudinal and transverse section of the normal/healthy and remodeled heart.

Figure 2. Teaching points: A brief over view of the role RAAS, norepinephrine, and endothelin function in cardiac fibrosis and remodeling.

Figure 3. Teaching points: Dissecting survival (β2 AR) and apoptotic pathway (β1 AR) via Gs-cAMP-PKA-Akt and Gi-PI3K-AktGβγ in β2 AR ligation and activation of PKA-independent/CamKII-mediated apoptosis pathway via β1 AR ligation.

Figure 4. Teaching points: Concept of G-protein mediated signal transduction. After receptor ligation, G-Protein is activated via the exchange of GDP/GTP and induces Gα and Gβγ subunits dissociation. This is the concept of activation of small Rho-GTPase protein, initiation MAPK signaling, cAMP signaling, and activation of PLC-β.

Figure 5. Teaching points: The signaling pathway of adrenergic receptors in human cardiac tissue. The ligation of these receptors induces activation of two different pathways via AC and PLC effectors in human myocyte.

Figure 6. Teaching points: ROS is involved in pathological changes of the heart via three different pathways, including PKC and PKB, MAPK, and TNFα. Activation of these pathways induce cardiac remodeling, cardiomyocytes hypertrophy, and superoxide production.

Figure 7. Teaching points: Different phases of myocardial wound healing in post-MI patient has been descried. There are four different phases including Phase I (up to 8 h), Phase II (up to 6 days) Phase III (up to one month) and Phase IV (years after MI). The major event in Phase I is cardiomyocyte apoptosis and necrosis, Phase II involves acute inflammation, in Phase III granulated tissue is formed and finally in Phase IV scars are formed.

Figure 8. Teaching points: TGFβ1 noncanonical signaling involves Ras/ERK1/2, p38, PI3K, Rho A signaling.

Figure 9. Teaching point: The protein Structure of Ski (TGF-β₁ transcriptional regulator) has been described. NH2 end of the protein plays a critical role in protein-protein interactions, and a R-Smad2/3 interacting domain that is important for Ski's ability to repress TGFβ/Smad-dependent signaling. The unique C2H2 (SAND) domain regulates interaction of Ski with Co-Smad4. The COOH terminal plays an important role in Ski:Sno homo- and hetero-dimerization as well as nuclear translocation of Ski [PRKRKLT – nuclear localization signal (NLS)].

Figure 10. Teaching points: Nuclear Ski can inhibit Smad-dependent signaling by (A) forming an inhibitory complex with the R-Smad/Co-Smad complex and stabilize them while bound to DNA. Ski can also repress TGFβ₁/Smad signaling from the cytoplasm in two ways. First, (B) Ski can form a complex with the Smad complex and prevent nuclear translocation. Second (C) Ski can prevent R-Smad phosphorylation at the level of the TβRI and prevent R-Smad complex formation at the initiating step.

Figure 11. Teaching points: Ski and Scx form a negative feedback loop that regulates their gene expression. In the chronic post-MI setting, it is believed that this balance is tipped in favour of Scx, which promotes repression of Ski transcription leading to remodelling of the cardiac matrix. With TGFβ₁ signaling unchecked by Ski, there is a significant increase in expression of fibrillar collagens and matrix proteins that ultimately cumulate to interstitial fibrosis and HF.

Figure 12. Teaching points: TGFβ₁ is considered an inducer of Scx expression. TGFβ₁ may exert its effects on Scx expression through a TGFβ₁ noncanonical (p44/42 MAPK) signaling pathway in combination with c-Jun activation in cardiac myofibroblasts. Smad proteins may still be involved in regulating Scx through an alternative unknown mechanism through inhibition of p44/42.

Figure 13. Teaching points: Application of biomaterial science and regenerative medicine in cardiovascular tissue engineering. We have showed (A) effect of stretching of highly elastic scaffold made from MeTro shows the role of extensible MeTro molecule with an asymmetric coil and a C-terminal cell interactive motif in this process. (B) Testing the effect of torsion on MeTro-based hydrogels shows how this hydrogel change structure before (left) and after 27 rotations (right). (C) This is obvious there is no breakage in the hydrogel structure after twisting. Reprinted with permission from (18). Copyright 2015, WILEY-VCH Verlag GmbH & Co. (D) 5 days Culturing cardiac fibroblasts on random and aligned electrospun scaffold (gelatin:PGS blend) confirms the normal structural and cytoskeletal properties of fibroblasts. This observation was made based on fluorescent images for α-SMA (red), F-actin (green), and DAPI (blue). Reprinted with permission from (260). Copyright 2013, Elsevier.